DDX3X

Summary

DDX3X (DEAD-box helicase 3 X-linked, HGNC:2745) is a protein-coding gene on chromosome Xp11.4, encoding ATP-dependent RNA helicase DDX3X (O00571). Multifunctional ATP-dependent RNA helicase. It is a selective cancer dependency (DepMap: 77.5% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the large DEAD-box protein family, that is defined by the presence of the conserved Asp-Glu-Ala-Asp (DEAD) motif, and has ATP-dependent RNA helicase activity. This protein has been reported to display a high level of RNA-independent ATPase activity, and unlike most DEAD-box helicases, the ATPase activity is thought to be stimulated by both RNA and DNA. This protein has multiple conserved domains and is thought to play roles in both the nucleus and cytoplasm. Nuclear roles include transcriptional regulation, mRNP assembly, pre-mRNA splicing, and mRNA export. In the cytoplasm, this protein is thought to be involved in translation, cellular signaling, and viral replication. Misregulation of this gene has been implicated in tumorigenesis. This gene has a paralog located in the nonrecombining region of the Y chromosome. Pseudogenes sharing similarity to both this gene and the DDX3Y paralog are found on chromosome 4 and the X chromosome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 1,128 total — 212 pathogenic, 126 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 12 cancer types
• Cancer dependency (DepMap): dependent in 77.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2745
Approved symbol	DDX3X
Name	DEAD-box helicase 3 X-linked
Location	Xp11.4
Locus type	gene with protein product
Status	Approved
Aliases	DBX, HLP2, DDX14, CAP-Rf
Ensembl gene	ENSG00000215301
Ensembl biotype	protein_coding
OMIM	300160
Entrez	1654

Gene structure

Transcript identifiers

Ensembl transcripts: 80 — 34 protein_coding, 29 retained_intron, 14 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000399959, ENST00000441189, ENST00000457138, ENST00000478993, ENST00000480592, ENST00000542215, ENST00000610559, ENST00000611546, ENST00000611968, ENST00000615313, ENST00000615742, ENST00000616050, ENST00000622198, ENST00000622373, ENST00000625837, ENST00000626301, ENST00000629496, ENST00000629785, ENST00000630255, ENST00000630370, ENST00000630858, ENST00000631641, ENST00000642161, ENST00000642322, ENST00000642424, ENST00000642589, ENST00000642597, ENST00000642624, ENST00000642687, ENST00000642722, ENST00000642763, ENST00000642793, ENST00000642801, ENST00000643820, ENST00000643821, ENST00000643963, ENST00000644073, ENST00000644074, ENST00000644109, ENST00000644260, ENST00000644307, ENST00000644513, ENST00000644677, ENST00000644876, ENST00000644958, ENST00000645080, ENST00000645120, ENST00000645253, ENST00000645338, ENST00000645380, ENST00000645561, ENST00000645574, ENST00000645589, ENST00000645783, ENST00000646093, ENST00000646107, ENST00000646122, ENST00000646196, ENST00000646223, ENST00000646319, ENST00000646390, ENST00000646627, ENST00000646679, ENST00000646822, ENST00000646940, ENST00000647219, ENST00000647286, ENST00000647373, ENST00000647477, ENST00000875783, ENST00000875784, ENST00000875785, ENST00000875786, ENST00000875787, ENST00000875788, ENST00000875789, ENST00000875790, ENST00000875791, ENST00000875792, ENST00000959626

RefSeq mRNA: 4 — MANE Select: NM_001356 NM_001193416, NM_001193417, NM_001356, NM_001363819

CCDS: CCDS43931, CCDS55404, CCDS87734, CCDS87736

Canonical transcript exons

ENST00000644876 — 17 exons

Exon	Start	End
ENSE00003474600	41346505	41346622
ENSE00003503118	41346229	41346410
ENSE00003511382	41345180	41345324
ENSE00003524328	41347312	41347451
ENSE00003537660	41345404	41345548
ENSE00003572608	41341484	41341616
ENSE00003577364	41339036	41339083
ENSE00003580051	41342495	41342653
ENSE00003586514	41342737	41342836
ENSE00003650940	41343216	41343351
ENSE00003656386	41337408	41337465
ENSE00003691105	41346859	41347012
ENSE00003713579	41344030	41344128
ENSE00003717628	41344239	41344399
ENSE00003721693	41343737	41343822
ENSE00003823838	41334162	41334297
ENSE00004021623	41347640	41350274

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 231.3902 / max 5213.3828, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196031	226.2378	1827
196030	2.4919	1165
196028	0.8086	463
196029	0.5294	293
196026	0.4473	231
209661	0.3452	169
196027	0.2907	112
196032	0.2393	91

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	99.82	gold quality
oocyte	CL:0000023	99.79	gold quality
sperm	CL:0000019	99.74	gold quality
secondary oocyte	CL:0000655	99.71	gold quality
male germ cell	CL:0000015	99.49	gold quality
palpebral conjunctiva	UBERON:0001812	99.40	gold quality
mammary duct	UBERON:0001765	99.38	gold quality
esophagus squamous epithelium	UBERON:0006920	99.38	gold quality
epithelium of mammary gland	UBERON:0003244	99.33	gold quality
tibia	UBERON:0000979	99.29	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.26	gold quality
skin of hip	UBERON:0001554	99.24	gold quality
colonic epithelium	UBERON:0000397	99.22	gold quality
amniotic fluid	UBERON:0000173	99.20	gold quality
upper leg skin	UBERON:0004262	99.18	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.17	gold quality
epithelium of esophagus	UBERON:0001976	99.16	gold quality
cauda epididymis	UBERON:0004360	99.14	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.10	gold quality
parotid gland	UBERON:0001831	99.09	gold quality
mucosa of urinary bladder	UBERON:0001259	99.08	gold quality
squamous epithelium	UBERON:0006914	99.08	gold quality
bone marrow cell	CL:0002092	99.07	gold quality
monocyte	CL:0000576	99.05	gold quality
mononuclear cell	CL:0000842	99.05	gold quality
seminal vesicle	UBERON:0000998	99.05	gold quality
trabecular bone tissue	UBERON:0002483	99.04	gold quality
leukocyte	CL:0000738	98.98	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.98	gold quality
mammary gland	UBERON:0001911	98.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	8.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CCNE1	Activation

Upstream regulators (CollecTRI, top): HIF1A, IRF3, TP53

miRNA regulators (miRDB)

279 targeting DDX3X, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 77.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Gene structure of the human DDX3 and chromosome mapping of its related sequences.Its organization was the same as that of the human DBY gene, a closely related sequence present on the Y chromosome. (PMID:11710523)
• DEAD box proteins and other RNA-binding proteins may play roles in active HIV replication and in the control of viral latency. (PMID:15588285)
• suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV- and HCV-associated pathogenesis (PMID:16301996)
• DDX3 suppresses tumor growth and transcriptionally activates the p21 promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells; DDX3 might be a candidate tumor suppressor. (PMID:16818630)
• can be used for rational design of selective inhibitors of hDDX3 (PMID:17357160)
• DDX3X is stabilized by AMP. (PMID:17631897)
• study demonstrates regulatory roles and action mechanisms for DDX3 in translation, cell growth and likely viral replication (PMID:17667941)
• DDX3 is required for hepatitis C virus RNA replication (PMID:17855521)
• the activation of DDX3 by BPDE can promote growth, proliferation and neoplastic transformation of breast epithelial cells (PMID:18264132)
• DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction. (PMID:18583960)
• DDX3 facilitates translation by resolving secondary structures of the 5’-untranslated region in mRNAs during ribosome scanning (PMID:18596238)
• Using RNA interference, DDX3 is shown to be required for expression of protein from reporter constructs. (PMID:18628297)
• DEAD box helicase is involved in TBK1/IKKepsilon-mediated IRF activation and Ifnb promoter induction. (PMID:18636090)
• studies have mapped the K7-binding region to a 30-residue N-terminal fragment of DDX3, ahead of the core RNA helicase domains (PMID:18845156)
• This review summarizes the data involving at least four different viruses (hepatitis C virus, hepatitis B virus, human immunodeficiency virus and poxviruses) that encode proteins that interact with DDX3 and manipulate its function. (PMID:19782656)
• This study shows for the first time that the requirement of DDX3 for hepatitis C virus replication is unrelated to its interaction with the viral core protein. (PMID:19793905)
• DDX3 can bind viral RNA to join it in the IPS-1 complex to up-regulate IFN-beta promoter activation. The 622-662 a.a DDX3 C-terminal region directly bound to the IPS-1 CARD-like domain. The whole DDX3 protein associated with RIG-I-like receptors. (PMID:20127681)
• HBV Pol inhibits TBK1/IKKepsilon activity by disrupting the interaction between IKKepsilon and DDX3 DEAD box RNA helicase, explaining how HBV evades innate immune response in the early phase of the infection (PMID:20657822)
• Results indicate that DDX3 is critical for translation of cyclin E1 mRNA, which provides an alternative mechanism for regulating cyclin E1 expression during the cell cycle. (PMID:20837705)
• Replication of HCV is significantly suppressed in cells expressing green fluorescent protein fusions to HCV core protein residues 16-36. (PMID:20862261)
• Hepatitis C virus core protein abrogates the DDX3 function that enhances IPS-1-mediated IFN-beta induction (PMID:21170385)
• Knockdown of DDX3 levels by shRNA reduced basal levels of Snail in HeLa and MCF-7 cells, and this was associated with reduced cell proliferation and migration. (PMID:21237216)
• HIV-1 Rev cofactors Sam68, eIF5A, hRIP, and DDX3 function in the translation of HIV-1 RNA; the regulatory mechanisms of HIV-1 RNA translation are likely different among these cofactors. (PMID:21360055)
• The role of DDX3 in antiviral immunity and its inhibition or exploitation by different viruses. (PMID:21428961)
• The role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region, is reported. (PMID:21448281)
• results identify a specific domain of DDX3 which may be suited as target for antiviral drugs designed to inhibit cellular cofactors for HIV-1 replication (PMID:21589879)
• DEAD-box RNA helicase DDX3 and the RNA interference pathway promote mitotic chromosome segregation. (PMID:21730191)
• The present study has characterized DDX3 as a pivotal SG-nucleating factor and illustrates co-ordinative roles for DDX3, eIF4E and PABP1 in integrating environmental stress with translational regulation. (PMID:21883093)
• Human Dead-box protein 3 (DDX3X), a RNA helicase regulating RNA splicing, export, transcription and translation was down-regulated upon MAT1A expression. (PMID:22270009)
• miR-98 and miR-181a through their regulatory functions on PGRMC1, PGR, CYP19A1, TIMP3, and DDX3X expression may influence a wide range of endometrial cellular activities during normal menstrual cycle and transition into disease states. (PMID:22492871)
• DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs (PMID:22872150)
• Positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well as poor-prognosis of gallbladder cancer. (PMID:23330003)
• Low/negative DDX3 expression in tumor cells was significantly associated with aggressive clinical manifestations and might be an independent survival predictor, particularly in non-smoker patients with OSCC (PMID:23410059)
• study identified DDX3 as a regulator of the Wnt-beta-catenin network, where it acts as a regulatory subunit of CK1epsilon: in a Wnt-dependent manner, DDX3 binds CK1epsilon and directly stimulates its kinase activity and promotes phosphorylation of the scaffold protein dishevelled (PMID:23413191)
• DDX3 is a scaffolding adaptor that directly facilitates phosphorylation of IRF3 by IKK-epsilon. (PMID:23478265)
• DDX3 is a new key molecule to understand the molecular mechanism underlying RNAi pathway in mammals. (PMID:23527197)
• DDX3 loss by p53 inactivation via MDM2/Slug/E-cadherin pathway promotes tumor malignancy and poor patient outcome (PMID:23584477)
• Results suggest that distinct DDX DEAD-box RNA helicases DDX3 and DDX5 cooperate to modulate the HIV-1 Rev function. (PMID:23608157)
• In pediatric T-acute lymphoblastic leukemia, we have identified 2 RNA processing genes, that is, HNRNPH1/5q35 and DDX3X/Xp11.3 as new MLLT10 fusion partners. (PMID:23673860)
• These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting. (PMID:23974721)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddx3xb	ENSDARG00000005774
danio_rerio	ddx3xa	ENSDARG00000020573
mus_musculus	Ddx3x	ENSMUSG00000000787
rattus_norvegicus	Ddx3x	ENSRNOG00000023383

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), DDX6 (ENSG00000110367), DDX55 (ENSG00000111364), DDX59 (ENSG00000118197), DDX54 (ENSG00000123064), DDX39A (ENSG00000123136), DDX27 (ENSG00000124228), DDX31 (ENSG00000125485), DDX56 (ENSG00000136271), EIF4A3 (ENSG00000141543), DDX46 (ENSG00000145833), DDX4 (ENSG00000152670), EIF4A2 (ENSG00000156976), DDX19B (ENSG00000157349), EIF4A1 (ENSG00000161960), DDX21 (ENSG00000165732), DDX19A (ENSG00000168872), TDRD12 (ENSG00000173809), DDX23 (ENSG00000174243), DDX10 (ENSG00000178105), DDX28 (ENSG00000182810), DDX41 (ENSG00000183258), DDX53 (ENSG00000184735), DDX51 (ENSG00000185163), DDX42 (ENSG00000198231), DDX39B (ENSG00000198563), DDX47 (ENSG00000213782), DDX52 (ENSG00000278053)

Protein

Protein identifiers

ATP-dependent RNA helicase DDX3X — O00571 (reviewed: O00571)

Alternative names: CAP-Rf, DEAD box protein 3, X-chromosomal, DEAD box, X isoform, Helicase-like protein 2

All UniProt accessions (26): A0A087WVZ1, A0A087WX09, A0A0D9SF53, A0A0D9SFB3, A0A0D9SG12, A0A0J9YVQ7, A0A2R8Y4A4, A0A2R8Y4D2, A0A2R8Y5G6, A0A2R8Y645, A0A2R8Y650, A0A2R8Y770, A0A2R8Y7T2, A0A2R8YCU0, A0A2R8YCW1, A0A2R8YDH3, A0A2R8YDT5, A0A2R8YF31, A0A2R8YF78, A0A2R8YF89, A0A2R8YFR4, A0A2R8YFS5, A0A2R8YGJ1, A0A2U3TZJ9, O00571, F6S8Q4

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional ATP-dependent RNA helicase. The ATPase activity can be stimulated by various ribo-and deoxynucleic acids indicative for a relaxed substrate specificity. In vitro can unwind partially double-stranded DNA with a preference for 5’-single-stranded DNA overhangs. Binds RNA G-quadruplex (rG4s) structures, including those located in the 5’-UTR of NRAS mRNA. Involved in many cellular processes, which do not necessarily require its ATPase/helicase catalytic activities. Involved in transcription regulation. Positively regulates CDKN1A/WAF1/CIP1 transcription in an SP1-dependent manner, hence inhibits cell growth. This function requires its ATPase, but not helicase activity. CDKN1A up-regulation may be cell-type specific. Binds CDH1/E-cadherin promoter and represses its transcription. Potentiates HNF4A-mediated MTTP transcriptional activation; this function requires ATPase, but not helicase activity. Facilitates HNF4A acetylation, possibly catalyzed by CREBBP/EP300, thereby increasing the DNA-binding affinity of HNF4 to its response element. In addition, disrupts the interaction between HNF4 and SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers. By promoting HNF4A-induced MTTP expression, may play a role in lipid homeostasis. May positively regulate TP53 transcription. Associates with mRNPs, predominantly with spliced mRNAs carrying an exon junction complex (EJC). Involved in the regulation of translation initiation. Not involved in the general process of translation, but promotes efficient translation of selected complex mRNAs, containing highly structured 5’-untranslated regions (UTR). This function depends on helicase activity. Might facilitate translation by resolving secondary structures of 5’-UTRs during ribosome scanning. Alternatively, may act prior to 43S ribosomal scanning and promote 43S pre-initiation complex entry to mRNAs exhibiting specific RNA motifs, by performing local remodeling of transcript structures located close to the cap moiety. Independently of its ATPase activity, promotes the assembly of functional 80S ribosomes and disassembles from ribosomes prior to the translation elongation process. Positively regulates the translation of cyclin E1/CCNE1 mRNA and consequently promotes G1/S-phase transition during the cell cycle. May activate TP53 translation. Required for endoplasmic reticulum stress-induced ATF4 mRNA translation. Independently of its ATPase/helicase activity, enhances IRES-mediated translation; this activity requires interaction with EIF4E. Independently of its ATPase/helicase activity, has also been shown specifically repress cap-dependent translation, possibly by acting on translation initiation factor EIF4E. Involved in innate immunity, acting as a viral RNA sensor. Binds viral RNAs and promotes the production of type I interferon (IFN-alpha and IFN-beta). Potentiate MAVS/RIGI-mediated induction of IFNB in early stages of infection. Enhances IFNB1 expression via IRF3/IRF7 pathway and participates in NFKB activation in the presence of MAVS and TBK1. Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFNB induction, acts as a scaffolding adapter that links IKBKE and IRF3 and coordinates their activation. Involved in the TLR7/TLR8 signaling pathway leading to type I interferon induction, including IFNA4 production. In this context, acts as an upstream regulator of IRF7 activation by MAP3K14/NIK and CHUK/IKKA. Stimulates CHUK autophosphorylation and activation following physiological activation of the TLR7 and TLR8 pathways, leading to MAP3K14/CHUK-mediated activatory phosphorylation of IRF7. Also stimulates MAP3K14/CHUK-dependent NF-kappa-B signaling. Negatively regulates TNF-induced IL6 and IL8 expression, via the NF-kappa-B pathway. May act by interacting with RELA/p65 and trapping it in the cytoplasm. May also bind IFNB promoter; the function is independent of IRF3. Involved in both stress and inflammatory responses. Independently of its ATPase/helicase activity, required for efficient stress granule assembly through its interaction with EIF4E, hence promotes survival in stressed cells. Independently of its helicase activity, regulates NLRP3 inflammasome assembly through interaction with NLRP3 and hence promotes cell death by pyroptosis during inflammation. This function is independent of helicase activity. Therefore DDX3X availability may be used to interpret stress signals and choose between pro-survival stress granules and pyroptotic NLRP3 inflammasomes and serve as a live-or-die checkpoint in stressed cells. In association with GSK3A/B, negatively regulates extrinsic apoptotic signaling pathway via death domain receptors, including TNFRSF10B, slowing down the rate of CASP3 activation following death receptor stimulation. Cleavage by caspases may inactivate DDX3X and relieve the inhibition. Independently of its ATPase/helicase activity, allosteric activator of CSNK1E. Stimulates CSNK1E-mediated phosphorylation of DVL2, thereby involved in the positive regulation of Wnt/beta-catenin signaling pathway. Also activates CSNK1A1 and CSNK1D in vitro, but it is uncertain if these targets are physiologically relevant. ATPase and casein kinase-activating functions are mutually exclusive. May be involved in mitotic chromosome segregation. (Microbial infection) Facilitates hepatitis C virus (HCV) replication. During infection, HCV core protein inhibits the interaction between MAVS and DDX3X and therefore impairs MAVS-dependent INFB induction and might recruit DDX3X to HCV replication complex. (Microbial infection) Facilitates HIV-1 replication. Acts as a cofactor for XPO1-mediated nuclear export of HIV-1 Rev RNAs. This function is strongly stimulated in the presence of TBK1 and requires DDX3X ATPase activity. (Microbial infection) Facilitates Zika virus (ZIKV) replication. (Microbial infection) Facilitates Dengue virus (DENV) replication. (Microbial infection) Facilitates Venezuelan equine encephalitis virus (VEEV) replication.

Subunit / interactions. Homodimer; can bind RNA as a monomer and as a dimer/oligomer. Interacts with TDRD3. Interacts (when phosphorylated at Ser-102) with IRF3; the interaction facilitates the phosphorylation and activation of IRF3 by IKBKE. Directly interacts with XPO1/CRM1. The interaction with XPO1/CMR1 is dependent on the DDX3X nuclear export signal motif and XPO1 interaction with GTPase RAN in its active GTP-bound form. Weakly interacts with TBKBP1/SINTBAD. Directly interacts with TRAF3; this interaction stimulates TRAF3 ‘Lys-63’ ubiquitination. Interacts with CSNK1E in a Wnt-dependent manner; this interaction greatly enhances CSNK1E affinity for ATP, stimulates its kinase activity and promotes CSNK1E-mediated DVL2 phosphorylation. In the presence of RNA, the interaction is decreased. Also interacts with CSNK1D and stimulates its kinase activity. Interacts with TRPV4; this interaction is decreased when the TRPV4 channel is activated, leading to DDX3X relocalization to the nucleus. Interacts with MAP3K14/NIK. Directly interacts with CHUK/IKKA after physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation. May associate with EIF4F complex, composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3. Directly interacts with EIF4E in an RNA-independent manner; this interaction enhances EIF4E cap-binding ability. Directly interacts with EIF4G1 in an RNA-independent manner. DDX3X competes with EIF4G1 for interaction with EIF4E. Interacts with EIF4A1 and EIF2S1 in an RNA-independent manner. Associates with the eukaryotic translation initiation factor 3 (eIF-3) complex, including with EIF3B and EIF3C subunits. Directly interacts with IKBKE/IKKE; this interaction stimulates IKBKE activating autophosphorylation and is induced upon viral infection. Interacts with TBK1. Interacts with SP1; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription. Interacts with GSK3A and GSK3B. Interacts with several death receptors, inclusing FAS, TNFRSF10A and TNFRSF10B. Recruited to TNFRSF10B in the absence of receptor stimulation. When TNFRSF10B is stimulated, further recruited to the receptor and cleaved by caspases. A large proteolytic fragment remains associated with TNFRSF10B. Interacts (via C-terminus) with NXF1/TAP; this interaction may be partly involved in DDX3X nuclear export and in NXF1 localization to stress granules. Identified in an mRNP complex, composed of at least DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1/2, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. The interaction with IGF2BP1/2 is RNA-dependent. Directly interacts with PABPC1/PABP1 in an RNA-independent manner. This interaction increases in stressed cells and decreases during cell recovery. Interacts (via C-terminus) with MAVS/IPS-1; this interaction occurs rapidly, but transiently after Sendai virus infection. The interaction potentiates MAVS-mediated IFNB induction. Interacts with ERCC6/CBS. Interacts with DHX33 in an RNA-independent manner. Interacts with DDX5 in the cytoplasm; this interaction may be more efficient when both proteins are unphosphorylated. Interacts with RIGI/RIG-1. Interacts with IFIH1/MDA5. Interacts with NCAPH; this interaction may be important for the NCAPH localization at condensing chromosomes during mitosis. Interacts with NLRP3 (via NACHT domain) under inflammasome-activating conditions. Interacts with CAPRIN1. Interacts with HNF4A and NR0B2/SHP in an RNA-independent manner; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers. Interacts with CREBBP/CBP. Interacts with EP300/p300. Interacts with gamma-tubulin. Interacts with phosphorylated TP53. Directly interacts with RELA/p65; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals. (Microbial infection) Interacts with hepatitis B virus (HBV) polymerase in the cytoplasm; this interaction may inhibit DDX3X interaction with the IKBKE/TBK1 complex, and hence impair IKBKE/TBK1-mediated increase in IFNB production. (Microbial infection) Directly interacts with hepatitis C virus (HCV) core protein in the cytoplasm. (Microbial infection) Interacts with vaccinia virus (VACV) protein K7. (Microbial infection) Interacts with HIV-1 protein Rev. (Microbial infection) Interacts with Venezuelan equine encephalitis virus non-structural protein 3.

Subcellular location. Cell membrane. Nucleus. Cytoplasm. Stress granule. Inflammasome. Cell projection. Lamellipodium. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Widely expressed. In testis, expressed in spermatids. Expressed in epidermis and liver (at protein level).

Post-translational modifications. Phosphorylated by TBK1; the phosphorylation is required for the synergistic induction of IFNB mediated by TBK1 and DDX3X. Phosphorylated by IKBKE at Ser-102 after ssRNA viral infection; enhances the induction of INFB promoter by IRF3. The cytoplasmic form is highly phosphorylated in the G1/S phase of the cell cycle and much less at G2/M. Phosphorylation by CSNK1E may inhibit RNA-stimulated ATPase activity. Upon stimulation of death receptors, including TNFRSF10B, recruited to receptors and cleaved by caspases. Proteolytic fragments remain associated with the receptors. This cleavage presumably inactivates DDX3X anti-apoptotic function. Ubiquitinated by RNF39 via ‘Lys-48’-linked ubiquitination; leading to proteasomal degradation.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Snijders Blok type (MRXSSB) [MIM:300958] A disorder characterized by mild to severe intellectual disability, hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Additionally, patients manifest variable non-neurologic features such as joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminus (residues 536-662) is dispensable for DDX3X trafficking.

Miscellaneous. Encoded by an chromosome X-linked gene which may escape X chromosome inactivation in females. DDX3Y, its homolog on chromosome Y, is located on the Y non-recombinant portion.

Similarity. Belongs to the DEAD box helicase family. DDX3/DED1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O00571-1	1	yes
O00571-2	2

RefSeq proteins (4): NP_001180345, NP_001180346, NP_001347, NP_001350748 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000629	RNA-helicase_DEAD-box_CS	Conserved_site
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00270, PF00271

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (164 total): mutagenesis site 34, modified residue 30, helix 23, sequence variant 22, strand 20, region of interest 12, compositionally biased region 6, turn 5, short sequence motif 3, domain 2, binding site 2, initiator methionine 1, chain 1, sequence conflict 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
3JRV	X-RAY DIFFRACTION	1.6
4O2C	X-RAY DIFFRACTION	1.8
4O2F	X-RAY DIFFRACTION	1.9
2JGN	X-RAY DIFFRACTION	1.91
4O2E	X-RAY DIFFRACTION	1.98
2I4I	X-RAY DIFFRACTION	2.2
5E7I	X-RAY DIFFRACTION	2.22
5E7J	X-RAY DIFFRACTION	2.23
7YMF	X-RAY DIFFRACTION	2.3
9E2C	X-RAY DIFFRACTION	2.3
5E7M	X-RAY DIFFRACTION	2.3
4PX9	X-RAY DIFFRACTION	2.31
8SSW	X-RAY DIFFRACTION	2.4
6O5F	X-RAY DIFFRACTION	2.5
6CZ5	X-RAY DIFFRACTION	3
7LIU	X-RAY DIFFRACTION	3
4PXA	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00571-F1	73.24	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 200–207; 224–231

Post-translational modifications (31): 2, 55, 82, 86, 90, 101, 102, 104, 110, 118, 131, 181, 183, 240, 269, 429, 438, 442, 456, 469 …

Mutagenesis-validated functional residues (34):

Position	Phenotype
230	complete loss of atpase and rna-unwinding activities. loss of hiv-1 mrna nuclear export. does not promote the translatio
240	greatly impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-1
269	greatly impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-1
275–277	increased nf-kappa-b-mediated transcriptional activity, contrary to wild-type which is inhibitory in this experimental s
347–350	loss of atpase activity.
347	no effect on general translation; when associated with a-200; a-207; a-230 and a-348.
348	no effect on general translation; when associated with a-200; a-207; a-230 and a-347.
348	loss of both atpase and rna helicase activities; decreased up-regulation of cdkn1a promoter activity and hnf4a-mediated
382–384	loss of rna helicase, but not atpase activity; no effect on the repression of cap- and ires-dependent translation, wnt/b
382	strong decrease in atpase activity and rna-unwinding activity. does not promote the translation of mrnas containing long
429	impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-438; a-44
438	impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-429; a-44
442	impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-429; a-43
456	impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-429; a-43
520	impairs phosphorylation by tbk1 and fails to synergize with tbk1 in ifn-beta induction; when associated with a-429; a-43
12–21	impairs nuclear export and interaction with xpo1/cmr1.
19–21	impairs nuclear export and interaction with xpo1/cmr1.
38	impaired interaction with eif4e; impaired stress granule formation, decreased repression of cap-dependent translation an
43	impaired interaction with eif4e; decreased repression of cap-dependent translation. fails to induce stress granule assem
55	partial loss of ubiquitination by rnf39.
71	reduces total phosphorylation by 60%. no effect on interaction with ikbke.
82–83	reduces total phosphorylation by 50%. no effect on interaction with ikbke.
84–85	loss of interaction with vacv protein k7, irf3 activation and ifnb1 promoter induction.
102	reduces total phosphorylation by 30%. abolishes interaction with irf3 and fails to enhance ifnb promoter induction. no e
102	interacts with irf3 and enhances ifnb promoter induction.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 784 (showing top): GGGACCA_MIR133A_MIR133B, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, ELVIDGE_HYPOXIA_DN, GOBP_RIBOSOME_BIOGENESIS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, AAGCAAT_MIR137, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497

GO Biological Process (50): cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), translational initiation (GO:0006413), chromosome segregation (GO:0007059), gamete generation (GO:0007276), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), response to virus (GO:0009615), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), Wnt signaling pathway (GO:0016055), negative regulation of translation (GO:0017148), cell differentiation (GO:0030154), positive regulation of cell growth (GO:0030307), negative regulation of cell growth (GO:0030308), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of type I interferon production (GO:0032481), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), stress granule assembly (GO:0034063), positive regulation of toll-like receptor 7 signaling pathway (GO:0034157), positive regulation of toll-like receptor 8 signaling pathway (GO:0034161), intracellular signal transduction (GO:0035556), positive regulation of translation in response to endoplasmic reticulum stress (GO:0036493), cytosolic ribosome assembly (GO:0042256), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), positive regulation of viral genome replication (GO:0045070), innate immune response (GO:0045087), positive regulation of translation (GO:0045727), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of translational initiation (GO:0045948), lipid homeostasis (GO:0055088), positive regulation of mitochondrial translation (GO:0070131), cellular response to arsenic-containing substance (GO:0071243), cellular response to osmotic stress (GO:0071470), positive regulation of chemokine (C-C motif) ligand 5 production (GO:0071651), positive regulation of canonical Wnt signaling pathway (GO:0090263), intrinsic apoptotic signaling pathway (GO:0097193), cellular response to virus (GO:0098586), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227)

GO Molecular Function (27): DNA binding (GO:0003677), DNA helicase activity (GO:0003678), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), GTPase activity (GO:0003924), ATP binding (GO:0005524), transcription factor binding (GO:0008134), poly(A) binding (GO:0008143), eukaryotic initiation factor 4E binding (GO:0008190), ATP hydrolysis activity (GO:0016887), ribonucleoside triphosphate phosphatase activity (GO:0017111), translation initiation factor binding (GO:0031369), RNA strand annealing activity (GO:0033592), signaling adaptor activity (GO:0035591), RNA stem-loop binding (GO:0035613), gamma-tubulin binding (GO:0043015), ribosomal small subunit binding (GO:0043024), CTPase activity (GO:0043273), protein serine/threonine kinase activator activity (GO:0043539), cadherin binding (GO:0045296), mRNA 5’-UTR binding (GO:0048027), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (21): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic stress granule (GO:0010494), lamellipodium (GO:0030027), cell leading edge (GO:0031252), secretory granule lumen (GO:0034774), P granule (GO:0043186), extracellular exosome (GO:0070062), NLRP3 inflammasome complex (GO:0072559), ficolin-1-rich granule lumen (GO:1904813), eukaryotic translation initiation factor 3 complex (GO:0005852), cytoskeleton (GO:0005856), membrane (GO:0016020), cytosolic small ribosomal subunit (GO:0022627), cell projection (GO:0042995), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
ribonucleoside triphosphate phosphatase activity	3
cytoplasm	3
positive regulation of cytokine production	2
translation	2
gene expression	2
regulation of gene expression	2
regulation of cell growth	2
cell growth	2
positive regulation of type I interferon production	2
positive regulation of pattern recognition receptor signaling pathway	2
positive regulation of intracellular signal transduction	2
nucleic acid binding	2
helicase activity	2
catalytic activity, acting on RNA	2
RNA binding	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasmic ribonucleoprotein granule	2
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
formation of translation initiation ternary complex	1
metabolic process	1
cell cycle process	1
sexual reproduction	1
multicellular organismal reproductive process	1
extrinsic apoptotic signaling pathway	1
response to other organism	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cellular developmental process	1
positive regulation of growth	1
positive regulation of cellular process	1
negative regulation of growth	1
negative regulation of cellular process	1
regulation of protein-containing complex assembly	1

Protein interactions and networks

STRING

5203 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDX3X	XPO1	O14980	992
DDX3X	TBK1	Q9UHD2	991
DDX3X	IKBKE	Q14164	991
DDX3X	EIF4E	P06730	979
DDX3X	EIF4G1	Q04637	958
DDX3X	CSNK1E	P49674	943
DDX3X	MAVS	Q7Z434	932
DDX3X	AGO2	Q9UKV8	848
DDX3X	PABPC1	P11940	826
DDX3X	BIRC2	Q13490	814
DDX3X	DDX5	P17844	810
DDX3X	CTNNB1	P35222	800
DDX3X	EIF2S1	P05198	794
DDX3X	DHX9	Q08211	794
DDX3X	DDX17	Q92841	783

IntAct

363 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
OPG044	DDX3X	psi-mi:“MI:0407”(direct interaction)	0.730
OPG044	DDX3X	psi-mi:“MI:0915”(physical association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
	DDX3X	psi-mi:“MI:0915”(physical association)	0.630
tat	DDX3X	psi-mi:“MI:0915”(physical association)	0.610
DDX3X	tat	psi-mi:“MI:0915”(physical association)	0.610
DDX3X	tat	psi-mi:“MI:0403”(colocalization)	0.610
YBX1	DDX3X	psi-mi:“MI:0403”(colocalization)	0.610
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
DDX3X	TFF2	psi-mi:“MI:0915”(physical association)	0.560
MZT2A	DDX3X	psi-mi:“MI:0915”(physical association)	0.560
DCANP1	DDX3X	psi-mi:“MI:0915”(physical association)	0.560
DDX3X	TARDBP	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (888): DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Reconstituted Complex), DDX3X (Affinity Capture-MS), DDX3X (Reconstituted Complex), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS), DDX3X (Affinity Capture-MS)

ESM2 similar proteins: A1CH78, A1CXK7, A2QI25, A3LQ01, A4RHF1, A5DQS0, A5DZE6, A6R3L3, A6SEH9, A6ZP47, A6ZWD3, A7EJY3, A7TKR8, C8V8H4, D0PV95, O00571, O13370, O15523, P06634, P0CQ74, P0CQ75, P16381, P24346, P24784, Q0CLJ6, Q1DJF0, Q2HBE7, Q2UGK3, Q4I7K4, Q4JG17, Q4P733, Q4WP13, Q5A4E2, Q5RF43, Q62095, Q62167, Q6BU54, Q6CB69, Q6CLR3, Q6FP38

Diamond homologs: A1C6C4, A1CH78, A1CXK7, A1DGZ7, A2QC74, A2QI25, A3LQ01, A3LQW7, A4QSS5, A4RHF1, A5DL80, A5DQS0, A5DS77, A5DZE6, A6R3L3, A6RGE3, A6SEH9, A6SFW7, A6ZP47, A6ZRX0, A6ZWD3, A7E449, A7EJY3, A7TKR8, C8V8H4, D0PV95, G0SFM2, O00571, O01836, O13370, O15523, P06634, P09052, P0CQ74, P0CQ75, P0CQ76, P0CQ77, P16381, P19109, P24346

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	DDX3X	phosphorylation
CyclinB/CDK1	down-regulates	DDX3X	phosphorylation
FUS	“down-regulates activity”	DDX3X	relocalization
DDX3X	“down-regulates activity”	EIF4E	binding
DDX3X	“up-regulates activity”	PABPC1	binding
DDX3X	“up-regulates activity”	SP1	binding
TBK1	“up-regulates activity”	DDX3X	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 164 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-2 modulates host translation machinery	5	10.8×	7e-03
SARS-CoV-1-host interactions	6	10.1×	3e-03
SARS-CoV-1 Infection	6	8.2×	7e-03
SARS-CoV-2-host interactions	7	8.0×	3e-03
Macroautophagy	6	6.7×	1e-02
Processing of Capped Intron-Containing Pre-mRNA	8	6.3×	4e-03
mRNA Polyadenylation	7	5.9×	9e-03
SARS-CoV-2 Infection	7	5.4×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	5	13.7×	7e-03
mitophagy	5	12.4×	7e-03
positive regulation of transcription elongation by RNA polymerase II	5	11.8×	7e-03
cellular response to UV	5	11.6×	7e-03
negative regulation of translation	7	10.7×	2e-03
regulation of circadian rhythm	5	10.1×	9e-03
G1/S transition of mitotic cell cycle	6	9.4×	7e-03
mRNA splicing, via spliceosome	8	5.7×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 12 cancer types — BL, BRCA, CLLSLL, DLBCLNOS, HNSC, LNM, MBL, MEL, MLYM, NHL, PAST, PLMESO.

Clinical variants and AI predictions

ClinVar

1128 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	212
Likely pathogenic	126
Uncertain significance	223
Likely benign	232
Benign	65

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064811	NM_001356.5(DDX3X):c.614C>T (p.Pro205Leu)	Pathogenic
1172650	NM_001356.5(DDX3X):c.1806C>G (p.Tyr602Ter)	Pathogenic
1184002	NM_001356.5(DDX3X):c.165dup (p.Asp56fs)	Pathogenic
1196594	NM_001356.5(DDX3X):c.453_454del (p.Ser152fs)	Pathogenic
1205549	NM_001356.5(DDX3X):c.875G>T (p.Arg292Leu)	Pathogenic
1210076	NM_001356.5(DDX3X):c.731C>G (p.Ser244Ter)	Pathogenic
1254780	NM_001356.5(DDX3X):c.1252_1255del (p.Gln417_Lys418insTer)	Pathogenic
1285558	NM_001356.5(DDX3X):c.1443dup (p.Glu482fs)	Pathogenic
1302008	NM_001356.5(DDX3X):c.71C>A (p.Ser24Ter)	Pathogenic
1320227	NM_001356.5(DDX3X):c.1025+1G>A	Pathogenic
1322193	NM_001356.5(DDX3X):c.1251_1252del (p.Lys418fs)	Pathogenic
1322194	NM_001356.5(DDX3X):c.1274C>G (p.Ser425Ter)	Pathogenic
1322195	NM_001356.5(DDX3X):c.930dup (p.Arg311fs)	Pathogenic
1325823	NM_001356.5(DDX3X):c.1693C>T (p.Gln565Ter)	Pathogenic
1325856	NM_001356.5(DDX3X):c.207T>G (p.Tyr69Ter)	Pathogenic
1330240	NM_001356.5(DDX3X):c.1463G>C (p.Arg488Pro)	Pathogenic
1331594	NM_001356.5(DDX3X):c.1733dup (p.His578fs)	Pathogenic
1331655	NM_001356.5(DDX3X):c.79_80insT (p.Gln27fs)	Pathogenic
1356409	NM_001356.5(DDX3X):c.565G>T (p.Glu189Ter)	Pathogenic
1452148	NM_001356.5(DDX3X):c.841C>T (p.Gln281Ter)	Pathogenic
1453556	NM_001356.5(DDX3X):c.1658_1661del (p.Thr553fs)	Pathogenic
1455310	NM_001356.5(DDX3X):c.645dup (p.Glu216fs)	Pathogenic
1676929	NM_001356.5(DDX3X):c.1299CCT[1] (p.Leu435del)	Pathogenic
1676940	NM_001356.5(DDX3X):c.151+1G>A	Pathogenic
1679537	NM_001356.5(DDX3X):c.1171-2A>G	Pathogenic
1685691	NM_001356.5(DDX3X):c.1264_1267del (p.Val422fs)	Pathogenic
1691603	NM_001356.5(DDX3X):c.1091T>G (p.Ile364Arg)	Pathogenic
1695343	NM_001356.5(DDX3X):c.233C>A (p.Ser78Ter)	Pathogenic
1701867	NM_001356.5(DDX3X):c.488dup (p.Tyr163Ter)	Pathogenic
1706558	NM_001356.5(DDX3X):c.1395_1399del (p.Tyr466fs)	Pathogenic

SpliceAI

2628 predictions. Top by Δscore:

Variant	Effect	Δscore
X:41337466:G:GG	donor_gain	1.0000
X:41341476:A:AG	acceptor_gain	1.0000
X:41341477:A:G	acceptor_gain	1.0000
X:41341479:CAAAG:C	acceptor_loss	1.0000
X:41341480:A:AG	acceptor_gain	1.0000
X:41341480:AAAG:A	acceptor_gain	1.0000
X:41341481:A:G	acceptor_gain	1.0000
X:41341482:A:AG	acceptor_gain	1.0000
X:41341482:AGGTT:A	acceptor_loss	1.0000
X:41341483:G:GG	acceptor_gain	1.0000
X:41341612:GGAAG:G	donor_gain	1.0000
X:41341613:GAAG:G	donor_gain	1.0000
X:41341613:GAAGG:G	donor_gain	1.0000
X:41341614:AAGG:A	donor_loss	1.0000
X:41341615:AG:A	donor_gain	1.0000
X:41341615:AGG:A	donor_loss	1.0000
X:41341616:GG:G	donor_gain	1.0000
X:41341617:G:GG	donor_gain	1.0000
X:41341947:A:G	acceptor_gain	1.0000
X:41342483:T:TA	acceptor_gain	1.0000
X:41342485:T:TA	acceptor_gain	1.0000
X:41342488:T:A	acceptor_gain	1.0000
X:41342491:TCA:T	acceptor_loss	1.0000
X:41342492:CAGGT:C	acceptor_loss	1.0000
X:41342493:A:AG	acceptor_gain	1.0000
X:41342493:A:C	acceptor_loss	1.0000
X:41342493:AG:A	acceptor_gain	1.0000
X:41342494:G:A	acceptor_gain	1.0000
X:41342494:G:GG	acceptor_gain	1.0000
X:41342494:GGT:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000269084 (X:41337874 A>G), RS1000353570 (X:41350826 A>G), RS1000421172 (X:41347119 G>GC), RS1000453447 (X:41360889 A>G), RS1000703025 (X:41338407 G>GA), RS1000798137 (X:41352510 C>A), RS1000898735 (X:41343308 T>C), RS1001015914 (X:41336072 T>C), RS1001054792 (X:41335785 C>G), RS1001070547 (X:41332104 T>C,G), RS1001272847 (X:41343542 T>C), RS1001317247 (X:41335489 G>A), RS1001358042 (X:41347661 A>G), RS1001408656 (X:41348092 C>G), RS1001524922 (X:41336711 C>T)

Disease associations

OMIM: gene MIM:300160 | disease phenotypes: MIM:300958, MIM:309510, MIM:213000, MIM:300534, MIM:155255

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 102	Definitive	X-linked
X-linked syndromic intellectual disability	Definitive	X-linked
Toriello-Carey syndrome	Supportive	Autosomal recessive
X-linked intellectual disability-hypotonia-movement disorder syndrome	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Definitive	XL

Mondo (10): intellectual disability, X-linked 102 (MONDO:0010497), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), X-linked syndromic intellectual disability (MONDO:0020119), X-linked intellectual disability-hypotonia-movement disorder syndrome (MONDO:0018709), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), syndromic X-linked intellectual disability Claes-Jensen type (MONDO:0010355), medulloblastoma (MONDO:0007959), microcephaly (MONDO:0001149), Toriello-Carey syndrome (MONDO:0009021)

Orphanet (8): X-linked intellectual disability-hypotonia-movement disorder syndrome (Orphanet:457260), Rare genetic intellectual disability (Orphanet:183757), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), KDM5C-related syndromic X-linked intellectual disability (Orphanet:85279), Medulloblastoma (Orphanet:616), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: X-linked syndromic intellectual disability (Orphanet:98464)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000174	Abnormal palate morphology
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000276	Long face
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000391	Thickened helices
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000752	Hyperactivity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_90	Refractive error	5.000000e-09

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
C562568	Cerebellar Hypoplasia (supp.)
C563127	Corpus Callosum, Agenesis of, with Facial Anomalies and Robin Sequence (supp.)
C564494	Mental Retardation, X-Linked, Syndromic, Jarid1c-Related (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5553 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 111,611 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL941	IMATINIB	4	111,611

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

90 potent at pChembl≥5 of 121 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL4633761
8.16	Kd	6.833	nM	CHEMBL5653589
8.16	ED50	6.833	nM	CHEMBL5653589
7.22	IC50	60	nM	CHEMBL4633565
7.22	IC50	60	nM	CHEMBL4642739
7.16	IC50	70	nM	CHEMBL5220761
7.10	IC50	80	nM	CHEMBL4644016
7.00	IC50	100	nM	CHEMBL4792698
7.00	Ki	100	nM	CHEMBL5219128
7.00	Ki	100	nM	CHEMBL5220346
6.92	IC50	120	nM	CHEMBL4591917
6.92	IC50	120	nM	CHEMBL4634423
6.92	IC50	120	nM	CHEMBL4764675
6.92	IC50	120	nM	CHEMBL5220068
6.85	IC50	140	nM	CHEMBL4743218
6.85	IC50	140	nM	CHEMBL5220029
6.82	IC50	150	nM	CHEMBL4744776
6.82	IC50	150	nM	CHEMBL5218961
6.77	IC50	170	nM	CHEMBL4639795
6.75	IC50	180	nM	CHEMBL4577525
6.70	IC50	200	nM	CHEMBL4648145
6.70	Ki	200	nM	CHEMBL5220328
6.70	IC50	200	nM	CHEMBL5220798
6.70	IC50	200	nM	CHEMBL5219645
6.52	IC50	300	nM	CHEMBL4531719
6.52	IC50	300	nM	CHEMBL4635553
6.52	IC50	300	nM	CHEMBL4635666
6.52	Ki	300	nM	CHEMBL5220743
6.52	Ki	300	nM	CHEMBL5220373
6.44	IC50	360	nM	CHEMBL4551611
6.40	IC50	400	nM	CHEMBL4571759
6.40	IC50	400	nM	CHEMBL4569026
6.40	IC50	400	nM	CHEMBL4533005
6.40	IC50	400	nM	CHEMBL4785115
6.40	Ki	400	nM	CHEMBL5219814
6.40	Ki	400	nM	CHEMBL5218532
6.40	IC50	400	nM	CHEMBL5219805
6.36	Kd	435	nM	IMATINIB
6.31	IC50	490	nM	CHEMBL4741968
6.30	Ki	500	nM	CHEMBL5220525
6.30	Ki	500	nM	CHEMBL5220538
6.22	IC50	600	nM	CHEMBL4640027
6.22	Ki	600	nM	CHEMBL5220211
6.22	IC50	600	nM	CHEMBL5220524
6.16	Ki	700	nM	CHEMBL5220991
6.10	IC50	800	nM	CHEMBL5219374
6.09	IC50	820	nM	CHEMBL4742331
6.05	IC50	890	nM	CHEMBL4741684
6.03	IC50	940	nM	CHEMBL4787707
6.00	IC50	1000	nM	CHEMBL2011807

PubChem BioAssay actives

88 with measured affinity, of 446 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
ethyl 3-[[3-[4-(ethoxymethyl)triazol-1-yl]phenyl]sulfonylamino]benzoate	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.0050	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148221: Binding affinity to human DDX3X incubated for 45 mins by Kinobead based pull down assay	kd	0.0068	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-[2-(methanesulfonamido)phenyl]urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.0600	uM
3-[4-(ethoxymethyl)triazol-1-yl]-N-(2-morpholin-4-ylphenyl)benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.0600	uM
1-[4-(5-butyl-1H-1,2,4-triazol-3-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1916931: Inhibition of recombinant DDX3X (unknown origin) helicase activity using dsRNA as substrate incubated for 40 mins by FRET assay	ic50	0.0700	uM
3-[4-(ethoxymethyl)triazol-1-yl]-N-[2-(methanesulfonamido)phenyl]benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.0800	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-[2-methyl-5-(oxolan-3-yloxy)phenyl]urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.1000	uM
2-[(E)-[[4-anilino-6-(2,2-diethylhydrazinyl)-1,3,5-triazin-2-yl]hydrazinylidene]methyl]phenol	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.1000	uM
N-(2-chlorophenyl)-3-[(5Z)-4-oxo-2-sulfanylidene-5-[(3,4,5-trimethoxyphenyl)methylidene]-1,3-thiazolidin-3-yl]propanamide	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.1000	uM
1-(2-fluorophenyl)-3-[4-[4-(3-methylbutyl)triazol-1-yl]phenyl]urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.1200	uM
1-isoquinolin-5-yl-3-[4-[4-(3-methylbutyl)triazol-1-yl]phenyl]urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.1200	uM
3-(4-butyltriazol-1-yl)-N-isoquinolin-5-ylbenzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.1200	uM
1-(2-fluorophenyl)-3-[4-[4-(2-methylpropyl)triazol-1-yl]phenyl]urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.1200	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(5-cyclopentyloxy-2-methylphenyl)urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.1400	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(2-cyclopentyloxyphenyl)urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.1400	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-isoquinolin-5-ylurea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.1500	uM
1-isoquinolin-6-yl-3-[4-[4-(2-methylpropyl)triazol-1-yl]phenyl]urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.1500	uM
1-[4-[4-(3-methylbutyl)triazol-1-yl]phenyl]-3-(2-methylphenyl)urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.1700	uM
3-(4-butyltriazol-1-yl)-N-(2-methoxyphenyl)benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.1800	uM
1-(3-fluorophenyl)-3-[4-[4-(3-methylbutyl)triazol-1-yl]phenyl]urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.2000	uM
1-(3-fluorophenyl)-3-[4-[4-(2-methylpropyl)triazol-1-yl]phenyl]urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.2000	uM
(5Z)-5-[[2-(2-hydroxyethylamino)-4-oxopyrido[1,2-a]pyrimidin-3-yl]methylidene]-3-(2-phenylethyl)-1,3-thiazolidine-2,4-dione	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.2000	uM
5-(1H-benzimidazol-2-ylamino)-2-hydroxybenzoic acid	1916932: Inhibition of recombinant DDX3X (unknown origin) helicase activity using 6-FAM-labeled dsRNA as substrate incubated for 30 mins by fluorescence based assay	ic50	0.2000	uM
1-[3-methoxy-4-[4-(3-methylbutyl)triazol-1-yl]phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.3000	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(2-methylphenyl)urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.3000	uM
1-[4-(4-hexyltriazol-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.3000	uM
N-(3-fluorophenyl)-3-[(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanamide	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.3000	uM
N-[4-[(E)-[(4,6-dianilino-1,3,5-triazin-2-yl)hydrazinylidene]methyl]phenyl]acetamide	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.3000	uM
N-(2-hydroxyphenyl)-3-nitrobenzenesulfonamide	1916932: Inhibition of recombinant DDX3X (unknown origin) helicase activity using 6-FAM-labeled dsRNA as substrate incubated for 30 mins by fluorescence based assay	ic50	0.3600	uM
3-(4-butyltriazol-1-yl)-N-(2-hydroxyphenyl)benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.4000	uM
2-[1-[4-[[2-(trifluoromethyl)phenyl]carbamoylamino]phenyl]triazol-4-yl]ethyl 3-methylbutanoate	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.4000	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.4000	uM
3-(4-butyltriazol-1-yl)-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.4000	uM
3-[4-(ethoxymethyl)triazol-1-yl]-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.4000	uM
2-[3-[(5Z)-5-(1,3-benzodioxol-5-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanoylamino]benzoic acid	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.4000	uM
2-[(E)-[[4-(3-chloroanilino)-6-(morpholin-4-ylamino)-1,3,5-triazin-2-yl]hydrazinylidene]methyl]phenol	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.4000	uM
Imatinib	1424975: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4350	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(5-hydroxy-2-methylphenyl)urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.4900	uM
N-(3,5-difluorophenyl)-3-[(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanamide	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.5000	uM
N-[4-[(E)-[[4-anilino-6-(benzylamino)-1,3,5-triazin-2-yl]hydrazinylidene]methyl]phenyl]acetamide	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.5000	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(3-fluorophenyl)urea	1655775: Inhibition of recombinant full length human His-tagged DDX3X expressed in Escherichia coli using dsRNA as substrate measured after 40 mins in presence of ATP by FRET assay	ic50	0.6000	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-(2-fluorophenyl)urea	1916930: Inhibition of DDX3X (unknown origin) helicase activity	ic50	0.6000	uM
2-[(E)-[[4-(benzylamino)-6-(morpholin-4-ylamino)-1,3,5-triazin-2-yl]hydrazinylidene]methyl]phenol	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.6000	uM
2-[(E)-[[4-[(4-fluorophenyl)methylamino]-6-(morpholin-4-ylamino)-1,3,5-triazin-2-yl]hydrazinylidene]methyl]phenol	1916928: Binding affinity to DDX3X (unknown origin) assessed as inhibition constant	ki	0.7000	uM
1-[4-(2-butyltetrazol-5-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1916931: Inhibition of recombinant DDX3X (unknown origin) helicase activity using dsRNA as substrate incubated for 40 mins by FRET assay	ic50	0.8000	uM
1-[4-(4-butyltriazol-1-yl)phenyl]-3-[5-(methoxymethoxy)-2-methylphenyl]urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.8200	uM
diethyl 2-[1-[4-[(2-methylphenyl)carbamoylamino]phenyl]triazol-4-yl]ethyl phosphate	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.8900	uM
[3-[[4-(4-butyltriazol-1-yl)phenyl]carbamoylamino]-4-methylphenyl] diethyl phosphate	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	0.9400	uM
1-[4-[4-(2-methoxyethyl)triazol-1-yl]phenyl]-3-(2-methylphenyl)urea	1692203: Inhibition of human DDX3X using dsRNA as substrate measured every 30 sec for 40 mins by FRET assay	ic50	1.0000	uM
1-[4-(5-butyl-1,3,4-oxadiazol-2-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea	1916931: Inhibition of recombinant DDX3X (unknown origin) helicase activity using dsRNA as substrate incubated for 40 mins by FRET assay	ic50	1.0000	uM

CTD chemical–gene interactions

79 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects reaction, increases reaction, decreases expression, affects activity, affects cotreatment (+4 more)	4
Tobacco Smoke Pollution	increases expression, affects expression	4
bisphenol A	decreases expression, increases expression, affects cotreatment, decreases methylation	3
Valproic Acid	increases methylation, decreases expression, increases expression	3
geldanamycin	increases degradation, increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
methacrylaldehyde	affects expression, affects oxidation, increases oxidation, increases abundance, affects cotreatment	2
Acrolein	affects cotreatment, affects expression, affects oxidation, increases oxidation, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Ozone	affects cotreatment, affects expression, affects oxidation, increases oxidation, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Antirheumatic Agents	decreases expression	2
Particulate Matter	increases expression, affects expression, increases abundance	2
aristolochic acid I	decreases expression	1
spautin-1	increases transport, affects cotreatment, decreases reaction, increases degradation, affects localization (+1 more)	1
2,4,6-tribromophenol	decreases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, affects oxidation, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
cobaltous chloride	decreases expression	1
ferrous chloride	increases expression	1
leupeptin	decreases reaction, increases degradation, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	decreases expression	1
aloxistatin	affects cotreatment, decreases reaction, increases degradation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 31 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003099	Binding	Inhibition of ATP dependent RNA unwinding activity of human RNA helicase DDX3	Ring expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication. — J Med Chem
CHEMBL4481332	ADMET	Inhibition of human DDX3X ATPase activity using DDX3 as substrate by ADP-Glo kinase assay	DDX3X Helicase Inhibitors as a New Strategy To Fight the West Nile Virus Infection. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 finite cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B9GV	Abcam A-549 DDX3X KO	Cancer cell line	Male
CVCL_IJ32	GM25952	Finite cell line	Female
CVCL_JF38	GM25974	Finite cell line	Female
CVCL_JF39	GM25975	Finite cell line	Female
CVCL_JF40	GM25976	Finite cell line	Male
CVCL_SK66	HAP1 DDX3X (-)	Cancer cell line	Male
CVCL_YN29	GM27192	Finite cell line	Female

Clinical trials (associated diseases)

203 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03718910	Not specified	COMPLETED	DDX3X Syndrome -The Seaver Autism Center for Research and Treatment is Characterizing DDX3X-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge