SAMHD1

Summary

SAMHD1 (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1, HGNC:15925) is a protein-coding gene on chromosome 20q11.23, encoding Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 (Q9Y3Z3). Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.

This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome.

Source: NCBI Gene 25939 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SAMHD1-related type 1 interferonopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,022 total — 94 pathogenic, 43 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15925
Approved symbol	SAMHD1
Name	SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	SBBI88, Mg11, HDDC1, MOP-5, AGS5
Ensembl gene	ENSG00000101347
Ensembl biotype	protein_coding
OMIM	606754
Entrez	25939

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 16 nonsense_mediated_decay, 13 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000262878, ENST00000465985, ENST00000642186, ENST00000642246, ENST00000642616, ENST00000643003, ENST00000643078, ENST00000643161, ENST00000643243, ENST00000643825, ENST00000643907, ENST00000643918, ENST00000644114, ENST00000644250, ENST00000644370, ENST00000644688, ENST00000645033, ENST00000645444, ENST00000646066, ENST00000646121, ENST00000646673, ENST00000646866, ENST00000646869, ENST00000646904, ENST00000647095, ENST00000647163, ENST00000647459, ENST00000682773, ENST00000683720, ENST00000683766, ENST00000866370, ENST00000866371, ENST00000866372, ENST00000866373, ENST00000926798, ENST00000970830, ENST00000970831

RefSeq mRNA: 3 — MANE Select: NM_015474 NM_001363729, NM_001363733, NM_015474

CCDS: CCDS13288, CCDS86953, CCDS86954

Canonical transcript exons

ENST00000646673 — 16 exons

Exon	Start	End
ENSE00000661812	36897822	36897959
ENSE00000661813	36898440	36898544
ENSE00000661815	36905364	36905503
ENSE00001622813	36911218	36911333
ENSE00001667406	36916949	36917049
ENSE00001711142	36912461	36912552
ENSE00001752622	36919364	36919519
ENSE00001793017	36916722	36916830
ENSE00003462531	36941039	36941111
ENSE00003535434	36930760	36930875
ENSE00003546823	36935029	36935189
ENSE00003598833	36927182	36927252
ENSE00003619308	36946738	36946804
ENSE00003692177	36904157	36904249
ENSE00003828814	36890229	36893066
ENSE00003903369	36951436	36951708

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.3990 / max 1593.0884, expressed in 1788 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187158	21.9408	1753
187159	14.8012	1594
187161	8.1769	674
187157	7.5907	1127
187160	1.1273	394
187163	0.9665	330
187162	0.7957	276

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.27	gold quality
mononuclear cell	CL:0000842	99.23	gold quality
pericardium	UBERON:0002407	99.23	gold quality
leukocyte	CL:0000738	99.21	gold quality
epithelium of nasopharynx	UBERON:0001951	99.13	gold quality
bronchial epithelial cell	CL:0002328	99.11	gold quality
nasopharynx	UBERON:0001728	99.11	gold quality
lower lobe of lung	UBERON:0008949	99.09	gold quality
palpebral conjunctiva	UBERON:0001812	99.05	gold quality
peripheral nervous system	UBERON:0000010	99.02	gold quality
tibial nerve	UBERON:0001323	99.02	gold quality
trigeminal ganglion	UBERON:0001675	98.93	gold quality
visceral pleura	UBERON:0002401	98.76	gold quality
superficial temporal artery	UBERON:0001614	98.67	gold quality
mucosa of stomach	UBERON:0001199	98.50	gold quality
granulocyte	CL:0000094	98.48	gold quality
parietal pleura	UBERON:0002400	98.44	gold quality
trabecular bone tissue	UBERON:0002483	98.41	gold quality
sural nerve	UBERON:0015488	98.22	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.12	gold quality
lower esophagus	UBERON:0013473	98.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.97	gold quality
right lung	UBERON:0002167	97.96	gold quality
amniotic fluid	UBERON:0000173	97.91	gold quality
pleura	UBERON:0000977	97.81	gold quality
secondary oocyte	CL:0000655	97.76	gold quality
vena cava	UBERON:0004087	97.76	gold quality
saphenous vein	UBERON:0007318	97.74	gold quality
oral cavity	UBERON:0000167	97.62	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	2155.52
E-CURD-6	yes	1428.25
E-MTAB-9801	yes	1121.56
E-MTAB-9067	yes	747.43
E-HCAD-6	yes	569.25
E-MTAB-7381	yes	526.18
E-HCAD-13	yes	346.78
E-MTAB-10018	yes	138.55
E-HCAD-4	yes	76.27
E-HCAD-1	yes	52.17
E-MTAB-10287	yes	44.78
E-HCAD-10	yes	39.95
E-CURD-46	yes	29.93
E-GEOD-135922	yes	27.74
E-MTAB-9221	yes	26.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, CEBPG, FOXA2, HR, IRF1, IRF2, IRF6, IRF8, KLF6, NFKB1, NFKBIA, SPI1, STAT2, STAT3, STAT5A, STAT6, TBXT, TP53, TXK, ZHX2

miRNA regulators (miRDB)

57 targeting SAMHD1, 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-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
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-150-5P	99.99	66.69	1976
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-190B-3P	99.33	68.29	1382

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• SAMHD1 mediates TNF-alpha stimulation of lung fibroblasts. (PMID:18546154)
• Study describes mutations in SAMHD1 as the cause of Aicardi-Goutieres syndrome (AGS) at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. (PMID:19525956)
• I510T mutation of p63 was detected in both RHS and AEC syndrome patients and mutation of S541 residue can lead to either RHS (S541Y) or AEC syndrome (S541F). (PMID:20156774)
• Arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Goutieres syndrome because of SAMHD1 mutations. (PMID:20358604)
• report on four adult siblings with c.490C>T (p.Arg164X) mutation in SAMHD1, a gene most recently described in Aicardi-Goutieres syndrome, on both alleles in all affected siblings (PMID:20842748)
• A homozygous deletion of the SAMHD1 gene caused atypical Aicardi-Goutieres syndrome, presenting in utero with white matter destruction and associated with multiple mtDNA deletions. (PMID:21102625)
• Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. (PMID:21204240)
• The inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis. (PMID:21402907)
• Vpx induces proteasomal degradation of SAMHD1 (PMID:21613998)
• conclude that intracerebral large artery disease is a common phenomenon in patients with SAMHD1 mutations (PMID:21633013)
• Vpx relieves the inhibition of lentivirus infection in macrophages by loading SAMHD1 onto the CRL4(DCAF1) E3 ubiquitin ligase, leading to highly efficient proteasome-dependent degradation of the protein (PMID:21720370)
• SAMHD1 functions as a myeloid-cell-specific HIV-1 restriction factor by inhibiting viral DNA synthesis.[Review] (PMID:21740548)
• human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate (PMID:22056990)
• Vpx targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication (PMID:22069334)
• we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection (PMID:22174685)
• Vpx prevented the SAMHD1-mediated decrease in dNTP concentration and induced the degradation of human and rhesus macaque SAMHD1 but had no effect on mouse SAMHD1 (PMID:22327569)
• Data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease. (PMID:22461318)
• Polymorphisms of SAMHD1 are unlikely to contribute to the infection and natural control of HIV-1 in European and African-American individuals. (PMID:22530776)
• Vpx degradation of SAMHD1 is sufficiently rapid to enable appropriate progression of reverse transcription in monocyte-derived macrophages (PMID:22589553)
• Cytoplasmic variants of SAMHD1 potently block lentiviral infection and are resistant to Vpx-mediated degradation. (PMID:22691373)
• In this Progress article, we describe how SAMHD1 regulates the pool of intracellular nucleotides to control HIV replication and the innate immune response. (PMID:22926205)
• SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. (PMID:22972397)
• SAMHD1 is targeted by HIV-2 Vpx for ubiquitination and degradation in the nucleus. (PMID:22973040)
• anti-HIV activity of SAMHD1 (PMID:22978176)
• Studies indicate that restriction factors APOBEC3G, TRIM5, Tetherin and SAMHD1 exhibit direct antiviral activity. (PMID:22999946)
• there are several Vpx residues required for SAMHD1 degradation (PMID:23076149)
• Here, authors identified SAMHD1 as the restriction factor preventing efficient HIV-1 viral DNA synthesis in non-cycling resting CD4+ T-cells. (PMID:23092122)
• Here, authors identified two naturally occurring splice variants lacking exons 8-9 and 14, respectively. (PMID:23092512)
• results showed that SAMHD1 blocks infection of HIV-2, feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), Equine infectious anemia virus (EIAV), N-tropic murine leukemia virus (N-MLV), and B-tropic murine leukemia virus (B-MLV) (PMID:23158101)
• SAMHD1-mediated reduction of the intracellular dNTP pool in DCs is a common mechanism of HIV-1 restriction in myeloid cells. Endogenous expression of SAMHD1 in primary DCs or CD4+ T-lymphocytes is not upregulated by type I IFNs. (PMID:23231760)
• SAMHD1, by controlling the sensitivity of monocyte-derived dendritic cells to HIV-1 infection during intercellular contacts, impacts their ability to sense the virus and to trigger an innate immune response. (PMID:23269793)
• The nuclease activity of SAMHD1 could represent an additional mechanism contributing to HIV-1 restriction and suppression of the autoimmune response through direct cleavage of viral and endogenous nucleic acids. (PMID:23364794)
• Mutations associated with Aicardi-Goutieres syndrome exhibit both impaired nucleic acid-binding and complex formation implicating interaction with nucleic acids as an integral aspect of SAMHD1 function. (PMID:23371319)
• Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells (PMID:23426363)
• SAMHD1 tetramers are the biologically active form of this dNTPase and provide new insights into the functional organization of SAMHD1. (PMID:23426366)
• The results suggest that SAMHD1 has broad anti-retroviral activity against which most viruses have not found an escape. (PMID:23497255)
• Effective immune control of viral replication in HIV-2-infected individuals is not associated with increased Vpx-mediated degradation of SAMHD1. (PMID:23497283)
• SAMHD1 overexpression induced by IL-12/IL-18 was not dependent on IFN-gamma. (PMID:23526823)
• SAMHD1 phosphorylated on residue T592 is unable to block retroviral infection. (PMID:23601106)
• The phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 is a key regulatory mechanism of its antiviral activity. (PMID:23602554)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	samhd1	ENSDARG00000071288
mus_musculus	Samhd1	ENSMUSG00000027639
rattus_norvegicus	Samhd1	ENSRNOG00000006418
drosophila_melanogaster	fal	FBGN0028380
caenorhabditis_elegans		WBGENE00022673

Protein

Protein identifiers

Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 — Q9Y3Z3 (reviewed: Q9Y3Z3)

Alternative names: Dendritic cell-derived IFNG-induced protein, Monocyte protein 5, SAM domain and HD domain-containing protein 1

All UniProt accessions (13): Q9Y3Z3, A0A2R8Y586, A0A2R8Y5D2, A0A2R8Y755, A0A2R8Y7R5, A0A2R8YCS7, A0A2R8YD90, A0A2R8YDI8, A0A2R8YF18, A0A2R8YF51, A0A2R8YFV6, A0A2R8YG48, A0A804HL67

UniProt curated annotations — full annotation on UniProt →

Function. Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks. Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses, such as HIV-1: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells. Likewise, suppresses LINE-1 retrotransposon activity. Not able to restrict infection by HIV-2 virus; because restriction activity is counteracted by HIV-2 viral protein Vpx. In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools. Phosphorylation at Thr-592 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks. Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication. Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation. Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity. Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation.

Subunit / interactions. Homodimer; in absence of GTP and dNTP. Homotetramer; in GTP- and dNTP-bound form. Interacts with MRE11; leading to stimulate the exonuclease activity of MRE11. Interacts with RBBP8/CtIP. Interacts (via its C-terminus) with CD81. (Microbial infection) Interacts with HIV-2 viral protein Vpx; promoting interaction with a E3 ubiquitin-protein ligase complex containing DCAF1, leading to subsequent ubiquitination and degradation of SAMHD1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Expressed in heart, skeletal muscle, spleen, liver, small intestine, placenta, lung and peripheral blood leukocytes. No expression is seen in brain and thymus.

Post-translational modifications. Phosphorylation at Thr-592 by CDK1 acts as a switch to control deoxynucleoside triphosphate (dNTPase)-dependent and -independent functions. Phosphorylation at Thr-592 takes place in cycling cells: it reduces the stability of the homotetramer, impairing the dNTPase activity and subsequent ability to restrict infection by viruses. It also inhibits ability to suppress LINE-1 retrotransposon activity. In contrast, phosphorylation at Thr-592 promotes DNA end resection at stalled replication forks in response to DNA damage. (Microbial infection) Phosphorylation at Thr-592 by Epstein-Barr virus kinase BGLF4 and human cytomegalovirus/HCMV UL97 leads to a reduced level of dCTPase and dTTPase activity and the loss of viral restriction. (Microbial infection) Ubiquitinated following interaction with HIV-2 viral protein Vpx; Vpx promotes interaction and with a DCX (DDB1-CUL4-X-box) E3 ubiquitin ligase, leading to proteasomal degradation.

Disease relevance. Aicardi-Goutieres syndrome 5 (AGS5) [MIM:612952] A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. The disease is caused by variants affecting the gene represented in this entry. Chilblain lupus 2 (CHBL2) [MIM:614415] A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated and regulated via the combined actions of GTP and dNTPs (dATP, dGTP, dTTP and dCTP): Allosteric site 1 binds GTP, while allosteric site 2 binds dNTP. Allosteric activation promotes the formation of highly active homotetramers. Phosphorylation at Thr-592 impairs homotetramerization, thereby inhibiting dNTPase activity, leading to reduced ability to restrict infection by viruses.

Cofactor. Binds 1 Mn(2+) ion per subunit.

Domain organisation. In human, and in contrast to mouse protein, the SAM domain is not required for deoxynucleoside triphosphate (dNTPase) activity and ability to restrict infection by viruses.

Induction. By IFNG/IFN-gamma. Up-regulated in TNF treated lung fibroblasts.

Miscellaneous. Catalytically inactive. Catalytically inactive.

Similarity. Belongs to the SAMHD1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y3Z3-1	1	yes
Q9Y3Z3-3	3, delta8-9
Q9Y3Z3-4	4, delta14

RefSeq proteins (3): NP_001350658, NP_001350662, NP_056289* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR003607	HD/PDEase_dom	Domain
IPR006674	HD_domain	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR050135	dGTPase-like	Family

Pfam: PF01966, PF07647

Enzyme classification (BRENDA):

• EC 3.1.5.B1 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 5 shown:

• dGTP + H2O = 2’-deoxyguanosine + triphosphate + H(+) (RHEA:15193)
• a 2’-deoxyribonucleoside 5’-triphosphate + H2O = a 2’-deoxyribonucleoside + triphosphate + H(+) (RHEA:46148)
• dATP + H2O = 2’-deoxyadenosine + triphosphate + H(+) (RHEA:67648)
• dTTP + H2O = thymidine + triphosphate + H(+) (RHEA:80079)
• dCTP + H2O = 2’-deoxycytidine + triphosphate + H(+) (RHEA:80083)

UniProt features (238 total): binding site 82, mutagenesis site 49, helix 40, strand 19, sequence variant 14, turn 10, modified residue 8, sequence conflict 4, cross-link 4, domain 2, splice variant 2, chain 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

76 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6DWD	X-RAY DIFFRACTION	1.7
4MZ7	X-RAY DIFFRACTION	1.8
4BZB	X-RAY DIFFRACTION	1.83
7LTT	X-RAY DIFFRACTION	1.9
6DW5	X-RAY DIFFRACTION	1.93
6DW4	X-RAY DIFFRACTION	1.99
4TNP	X-RAY DIFFRACTION	2
6TX0	X-RAY DIFFRACTION	2.01
4QFY	X-RAY DIFFRACTION	2.1
4QG4	X-RAY DIFFRACTION	2.1
4RXP	X-RAY DIFFRACTION	2.1
4RXQ	X-RAY DIFFRACTION	2.1
4TO4	X-RAY DIFFRACTION	2.1
6U6Z	X-RAY DIFFRACTION	2.1
4RXR	X-RAY DIFFRACTION	2.12
6CM2	X-RAY DIFFRACTION	2.14
4QFX	X-RAY DIFFRACTION	2.2
4QG1	X-RAY DIFFRACTION	2.2
4RXS	X-RAY DIFFRACTION	2.2
4TO3	X-RAY DIFFRACTION	2.2
6DW3	X-RAY DIFFRACTION	2.2
6XU1	X-RAY DIFFRACTION	2.2
4QG2	X-RAY DIFFRACTION	2.25
6TXF	X-RAY DIFFRACTION	2.25
4TO2	X-RAY DIFFRACTION	2.27
7A5Y	X-RAY DIFFRACTION	2.29
4QFZ	X-RAY DIFFRACTION	2.3
4QG0	X-RAY DIFFRACTION	2.3
4TO0	X-RAY DIFFRACTION	2.3
4ZWG	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3Z3-F1	88.45	0.75

Functional residue map

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

Catalytic / active sites (1): 233

Ligand- & substrate-binding residues (82): 119 (in chain b); 119 (in chain b); 137 (in chain b); 142 (in chain b); 145 (in chain b); 149; 149; 149; 149; 150; 156 (in chain c); 156 (in chain c) …

Post-translational modifications (12): 1, 18, 21, 25, 33, 93, 592, 592, 467, 469, 492, 622

Mutagenesis-validated functional residues (49):

Position	Phenotype
77	increased stability of the tetramer and increased deoxynucleoside triphosphate (dntpase) activity; when associated with
80	increased stability of the tetramer and increased deoxynucleoside triphosphate (dntpase) activity; when associated with
111	increased stability of the tetramer and increased deoxynucleoside triphosphate (dntpase) activity; when associated with
137	impairs homotetramerization and nearly abolishes dntpase activity.
142	impairs homotetramerization and nearly abolishes dntpase activity; when associated with k-145.
143	abolished ability to restrict infection by viruses.
145	impairs homotetramerization and nearly abolishes dntpase activity. abolished ability to restrict infection by viruses.
145	impairs homotetramerization and nearly abolishes dntpase activity; when associated with e-145.
149	abolished dntpase activity without affecting homotetramerization. abolished dntpase activity; when associated with a-319
164	abolished ability to restrict infection by viruses.
167	abolished ability to restrict infection by viruses.
206–207	abolishes zinc binding and dntpase activity. does not affect ability to promote dna end resection at stalled replication
206	abolished ability to restrict infection by viruses.
207	abolished ability to restrict infection by viruses.
207	loss of dntpase activity.
210	abolished dntpase activity without affecting homotetramerization.
215	abolished dntpase activity without affecting homotetramerization.
226	loss of function in defense response to virus.
233	abolished dntpase activity without affecting homotetramerization. abolished ability to restrict infection by viruses.
311	loss of function in defense response to virus. loss of dntpase activity. does not affect oligomerization.
312	abolishes dntpase activity; when associated with a-315 and a-366. does not affect ability to promote dna end resection a
315	abolished ability to restrict infection by viruses. abolishes dntpase activity; when associated with a-312 and a-366. do
319	abolishes dntpase activity; when associated with a-149.
321	abolished ability to restrict infection by viruses.
330	impaired homotetramerization and slightly reduced dntpase activity. impaired homotetramerization and reduced dntpase act

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-8956319	Nucleotide catabolism
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-168256	Immune System
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 574 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOMF_RNA_NUCLEASE_ACTIVITY, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_PROTEIN_HOMOTETRAMERIZATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, BROWNE_HCMV_INFECTION_8HR_UP, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, MORI_IMMATURE_B_LYMPHOCYTE_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN

GO Biological Process (16): double-strand break repair via homologous recombination (GO:0000724), dGTP catabolic process (GO:0006203), immune response (GO:0006955), DNA damage response (GO:0006974), deoxyribonucleotide catabolic process (GO:0009264), somatic hypermutation of immunoglobulin genes (GO:0016446), innate immune response (GO:0045087), regulation of innate immune response (GO:0045088), dATP catabolic process (GO:0046061), protein homotetramerization (GO:0051289), defense response to virus (GO:0051607), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), DNA strand resection involved in replication fork processing (GO:0110025), immune system process (GO:0002376), DNA replication (GO:0006260), DNA repair (GO:0006281)

GO Molecular Function (16): nucleic acid binding (GO:0003676), single-stranded DNA binding (GO:0003697), RNA binding (GO:0003723), RNA nuclease activity (GO:0004540), GTP binding (GO:0005525), zinc ion binding (GO:0008270), dGTPase activity (GO:0008832), dGTP binding (GO:0032567), identical protein binding (GO:0042802), deoxynucleoside triphosphate hydrolase activity (GO:0106375), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), triphosphoric monoester hydrolase activity (GO:0016793), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), site of double-strand break (GO:0035861), tetraspanin-enriched microdomain (GO:0097197), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of nucleotides	1
Interferon Signaling	1
Immune System	1
Metabolism	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	3
purine deoxyribonucleotide catabolic process	2
deoxyribonucleoside triphosphate catabolic process	2
purine deoxyribonucleoside triphosphate catabolic process	2
binding	2
triphosphoric monoester hydrolase activity	2
cellular anatomical structure	2
recombinational repair	1
double-strand break repair	1
dGTP metabolic process	1
immune system process	1
response to stimulus	1
cellular response to stress	1
catabolic process	1
deoxyribonucleotide metabolic process	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immunoglobulins	1
immune response	1
defense response to symbiont	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
dATP metabolic process	1
protein homooligomerization	1
protein tetramerization	1
defense response	1
response to virus	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
replication fork processing	1
5’-3’ DNA exonuclease activity	1
biological_process	1
DNA biosynthetic process	1
DNA damage response	1
DNA binding	1
nucleic acid binding	1

Protein interactions and networks

STRING

1794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SAMHD1	RNASEH2A	O75792	967
SAMHD1	RNASEH2C	Q8TDP1	965
SAMHD1	RNASEH2B	Q5TBB1	950
SAMHD1	TREX1	Q9NSU2	918
SAMHD1	TRIM5	Q9C035	884
SAMHD1	APOBEC3G	Q9HC16	876
SAMHD1	DCAF1	Q9Y4B6	850
SAMHD1	BST2	Q10589	791
SAMHD1	MX2	P20592	790
SAMHD1	DDB1	Q16531	734
SAMHD1	IFNA13	P01562	718
SAMHD1	ADAR	P55265	718
SAMHD1	CCNL2	Q96S94	702
SAMHD1	IFNAR1	P17181	686
SAMHD1	CUL4A	Q13619	675

IntAct

114 interactions, top by confidence:

A	B	Type	Score
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
SAMHD1	SAMHD1	psi-mi:“MI:0407”(direct interaction)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DCAF1	vpx	psi-mi:“MI:0407”(direct interaction)	0.670
DCAF1	vpx	psi-mi:“MI:0915”(physical association)	0.670
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
SAMHD1	CDK2	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
POLR3H	POLR3A	psi-mi:“MI:0914”(association)	0.530
LGALS3BP	SAMHD1	psi-mi:“MI:0915”(physical association)	0.500
TIRAP	SAMHD1	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
NAA10	OFD1	psi-mi:“MI:0914”(association)	0.480
	CUL4A	psi-mi:“MI:0914”(association)	0.460
	AP3D1	psi-mi:“MI:0914”(association)	0.460

BioGRID (278): SAMHD1 (Affinity Capture-MS), SAMHD1 (Affinity Capture-MS), SAMHD1 (Biochemical Activity), SAMHD1 (Affinity Capture-MS), FAM13B (Two-hybrid), SAMHD1 (Two-hybrid), EEF1A1 (Two-hybrid), ACTB (Reconstituted Complex), EEF1A1 (Reconstituted Complex), EEF1A1 (Co-localization), RBX1 (Affinity Capture-Western), CUL4A (Affinity Capture-Western), SAMHD1 (Affinity Capture-Western), SAMHD1 (Affinity Capture-MS), CCNL2 (Affinity Capture-Western)

ESM2 similar proteins: A2VDQ5, A4IG42, A6H611, A8E657, A8WFT6, A9RBS1, F4HTQ1, F4KDA5, O22190, P24155, P24527, P30349, P42675, P42676, P47788, P52888, P55786, Q01992, Q02038, Q09152, Q0VCA5, Q11011, Q1JPJ8, Q1MTD3, Q28FT4, Q32PX9, Q3T0H0, Q3V384, Q502K2, Q54DD2, Q56H28, Q5R9V6, Q5U5V2, Q6INN8, Q6P4Z6, Q6PB06, Q6S9C8, Q8BH66, Q8C1A5, Q8GWT4

Diamond homologs: B0G107, P39651, P47699, Q09374, Q0VCA5, Q502K2, Q58554, Q5UQ48, Q5ZJL9, Q60710, Q6INN8, Q9Y3Z3, O05502

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	SAMHD1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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.

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	16.1×	1e-02
G1/S transition of mitotic cell cycle	6	10.8×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PCM.

Clinical variants and AI predictions

ClinVar

1022 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	94
Likely pathogenic	43
Uncertain significance	352
Likely benign	429
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032693	NM_015474.4(SAMHD1):c.1609-1G>T	Pathogenic
1069266	NM_015474.4(SAMHD1):c.1419del (p.Asp472_Tyr473insTer)	Pathogenic
1070389	NC_000020.10:g.(?35563422)(35563602_?)del	Pathogenic
1071265	NM_015474.4(SAMHD1):c.1334dup (p.Leu445fs)	Pathogenic
1071571	NM_015474.4(SAMHD1):c.1567A>T (p.Lys523Ter)	Pathogenic
1072306	NM_015474.4(SAMHD1):c.568_577del (p.Gln190fs)	Pathogenic
1074516	NM_015474.4(SAMHD1):c.328del (p.Ile110fs)	Pathogenic
1076079	NM_015474.4(SAMHD1):c.1321dup (p.Ala441fs)	Pathogenic
1180534	GRCh37/hg19 20q11.23(chr20:35577194-35586176)x1	Pathogenic
126403	Single allele	Pathogenic
126406	NM_015474.4(SAMHD1):c.1324C>T (p.Arg442Ter)	Pathogenic
126407	NM_015474.4(SAMHD1):c.1411-2A>G	Pathogenic
126413	NM_015474.4(SAMHD1):c.649_650insG (p.Phe217fs)	Pathogenic
1359912	NM_015474.4(SAMHD1):c.460del (p.Tyr154fs)	Pathogenic
1399339	NM_015474.4(SAMHD1):c.196A>T (p.Lys66Ter)	Pathogenic
1410719	NM_015474.4(SAMHD1):c.638_647del (p.Phe213fs)	Pathogenic
1411720	NM_015474.4(SAMHD1):c.1123C>T (p.Gln375Ter)	Pathogenic
1411961	NC_000020.10:g.(?35563412)(35569534_?)del	Pathogenic
1417058	NM_015474.4(SAMHD1):c.181G>T (p.Glu61Ter)	Pathogenic
1453548	NM_015474.4(SAMHD1):c.703C>T (p.Gln235Ter)	Pathogenic
1453957	NC_000020.10:g.(?35575121)(35580046_?)del	Pathogenic
1455178	NM_015474.4(SAMHD1):c.127A>T (p.Lys43Ter)	Pathogenic
1455349	NM_015474.4(SAMHD1):c.101dup (p.Leu36fs)	Pathogenic
1455381	NM_015474.4(SAMHD1):c.1444_1453del (p.Ser482fs)	Pathogenic
1456508	NC_000020.10:g.(?35521335)(35580046_?)del	Pathogenic
1456830	NM_015474.4(SAMHD1):c.1435G>T (p.Glu479Ter)	Pathogenic
1459517	NM_015474.4(SAMHD1):c.602_625+196delinsGAAATT	Pathogenic
1459644	NM_015474.4(SAMHD1):c.1034del (p.Asn345fs)	Pathogenic
1459871	NM_015474.4(SAMHD1):c.861T>A (p.Tyr287Ter)	Pathogenic
1677234	NC_000020.10:g.(35575208_35579838)(35580247?)del	Pathogenic

SpliceAI

2853 predictions. Top by Δscore:

Variant	Effect	Δscore
20:36904150:TAC:T	donor_loss	1.0000
20:36904151:A:AC	donor_gain	1.0000
20:36904151:ACT:A	donor_loss	1.0000
20:36904152:C:CC	donor_gain	1.0000
20:36904152:CTT:C	donor_loss	1.0000
20:36904153:T:TC	donor_loss	1.0000
20:36904154:TA:T	donor_loss	1.0000
20:36904155:A:AC	donor_gain	1.0000
20:36904155:ACAT:A	donor_gain	1.0000
20:36904155:ACATC:A	donor_gain	1.0000
20:36904156:C:CA	donor_gain	1.0000
20:36904156:C:G	donor_loss	1.0000
20:36904156:CA:C	donor_gain	1.0000
20:36904156:CAT:C	donor_gain	1.0000
20:36904156:CATC:C	donor_gain	1.0000
20:36904156:CATCC:C	donor_gain	1.0000
20:36904245:TCCTC:T	acceptor_gain	1.0000
20:36904246:CCTCC:C	acceptor_gain	1.0000
20:36904249:CCT:C	acceptor_loss	1.0000
20:36904250:C:CC	acceptor_gain	1.0000
20:36904250:CT:C	acceptor_loss	1.0000
20:36904251:T:C	acceptor_loss	1.0000
20:36911216:A:AG	donor_loss	1.0000
20:36911332:TC:T	acceptor_gain	1.0000
20:36911333:CC:C	acceptor_gain	1.0000
20:36911342:CATTT:C	acceptor_gain	1.0000
20:36912455:TCTTA:T	donor_loss	1.0000
20:36912456:CTTAC:C	donor_loss	1.0000
20:36912457:TTACA:T	donor_loss	1.0000
20:36912458:TACAT:T	donor_loss	1.0000

AlphaMissense

4152 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:36916830:C:A	R318S	0.997
20:36916830:C:G	R318S	0.997
20:36916949:C:A	R318M	0.997
20:36916965:A:G	W313R	0.997
20:36916965:A:T	W313R	0.997
20:36930774:A:G	L204P	0.997
20:36935034:A:C	S168R	0.997
20:36935034:A:T	S168R	0.997
20:36935036:T:G	S168R	0.997
20:36897916:C:G	R551P	0.996
20:36912503:C:G	R371P	0.996
20:36912518:C:G	R366P	0.996
20:36916949:C:G	R318T	0.996
20:36930772:A:G	C205R	0.996
20:36935104:C:G	R145P	0.996
20:36935110:C:G	R143P	0.996
20:36935111:G:T	R143S	0.996
20:36897933:A:C	F545L	0.995
20:36897933:A:T	F545L	0.995
20:36897935:A:G	F545L	0.995
20:36916828:T:A	D319V	0.995
20:36916829:C:G	D319H	0.995
20:36916962:C:G	D314H	0.995
20:36930789:A:T	V199D	0.995
20:36930862:C:G	A175P	0.995
20:36935067:A:C	F157L	0.995
20:36935067:A:T	F157L	0.995
20:36935069:A:G	F157L	0.995
20:36898488:G:C	F520L	0.994
20:36898488:G:T	F520L	0.994

dbSNP variants (sampled 300 via entrez): RS1000012025 (20:36925348 G>A), RS1000063381 (20:36891293 G>A), RS1000125373 (20:36915284 A>C,G), RS1000176347 (20:36941355 CTT>C), RS1000182986 (20:36943778 A>G), RS1000193706 (20:36934423 C>A,G), RS1000224521 (20:36934193 T>C), RS1000264272 (20:36931921 G>A), RS1000378891 (20:36941331 C>T), RS1000414481 (20:36938299 T>C), RS1000430750 (20:36895109 G>A), RS1000502034 (20:36951941 A>T), RS1000526140 (20:36936193 T>C), RS1000557220 (20:36935867 G>A), RS1000570351 (20:36899896 C>T)

Disease associations

OMIM: gene MIM:606754 | disease phenotypes: MIM:612952, MIM:225750, MIM:614415, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
Aicardi-Goutieres syndrome 5	Definitive	Autosomal recessive
Moyamoya disease	Strong	Autosomal recessive
familial chilblain lupus	Supportive	Autosomal dominant
Aicardi-Goutieres syndrome	Supportive	Autosomal dominant
chilblain lupus 2	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
SAMHD1-related type 1 interferonopathy	Definitive	AR

Mondo (7): Aicardi-Goutieres syndrome 5 (MONDO:0013059), Aicardi-Goutieres syndrome (MONDO:0018866), chilblain lupus 2 (MONDO:0013739), plasma cell myeloma (MONDO:0009693), cerebral palsy (MONDO:0006497), Moyamoya disease (MONDO:0016820), familial chilblain lupus (MONDO:0018827)

Orphanet (3): Aicardi-Goutières syndrome (Orphanet:51), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000252	Microcephaly
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000625	Eyelid coloboma
HP:0000639	Nystagmus
HP:0000737	Irritability
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000958	Dry skin
HP:0000965	Cutis marmorata
HP:0000992	Cutaneous photosensitivity
HP:0001063	Acrocyanosis
HP:0001087	Developmental glaucoma
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001357	Plagiocephaly
HP:0001369	Arthritis
HP:0001371	Flexion contracture
HP:0001433	Hepatosplenomegaly

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008163_459	Height	4.000000e-07
GCST011126_34	Caffeine consumption from coffee or tea	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D009072	Moyamoya Disease	C10.228.140.300.200.600; C10.228.140.300.510.200.737; C14.907.137.615; C14.907.253.123.620; C14.907.253.560.200.737
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
C535607	Aicardi-Goutieres syndrome (supp.)
C535608	Aicardi-Goutieres syndrome 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523507 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs8124728	Toxicity	3	stavudine	HIV infectious disease;Peripheral Nervous System Diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8124728	SAMHD1, TLDC2	3	2.75	1	stavudine
rs1891643	SAMHD1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Nucleoside synthesis and metabolism

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
NVP-BHG712	Inhibition	8.44	pKd
TH6342	Inhibition	5.24	pIC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.44	Kd	3.627	nM	CHEMBL3752910
8.44	ED50	3.627	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 6100 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149338: Binding affinity to human SAMHD1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0036	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
methylmercuric chloride	decreases expression, increases expression	3
Nickel	decreases expression, increases expression	3
bisphenol F	affects cotreatment, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	increases expression	2
Air Pollutants	affects cotreatment, affects expression, increases abundance, decreases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
bufotalin	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
bisphenol A	increases methylation	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
titanium dioxide	increases expression	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases expression	1
4-hydroxy-2-nonenal	affects binding	1
deoxyguanosine triphosphate	decreases abundance	1

ChEMBL screening assays

4 unique, capped per target: 3 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4420589	Binding	Substrate activity at SAMHD1 in human THP1 cells assessed as reduction in cytarabine triphosphate formation at 10 ug/ml incubated for 6 hrs by liquid chromatography tandem mass spectrometry relative to control human THP1 cells with CRISP/CA	Samhd1 modulation for treating resistance to cancer therapy
CHEMBL5483194	Functional	Compound was evaluated for the inhibition of human recombinant SAMHD1 at 5uM in a enzyme-coupled malachite green assay	Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel — iScience

Cellosaurus cell lines

15 cell lines: 9 induced pluripotent stem cell, 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C1P4	CRTDi008-A	Induced pluripotent stem cell	Male
CVCL_C1P5	CRTDi009-A	Induced pluripotent stem cell	Female
CVCL_C1P6	CRTDi009-B	Induced pluripotent stem cell	Female
CVCL_C1P7	CRTDi010-A	Induced pluripotent stem cell	Male
CVCL_C4SB	CRTDi010-B	Induced pluripotent stem cell	Male
CVCL_C4SC	CRTDi008-B	Induced pluripotent stem cell	Male
CVCL_D7ZY	Ubigene A-549 SAMHD1 KO	Cancer cell line	Male
CVCL_D9RA	Ubigene HEK293 SAMHD1 KO	Transformed cell line	Female
CVCL_E8F8	THP1-Dual KO-SAMHD1	Cancer cell line	Male
CVCL_TK00	HAP1 SAMHD1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study
NCT05722405	PHASE4	RECRUITING	Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma
NCT05855122	PHASE4	UNKNOWN	Safety and ASCT-related Symptom Burden Optimization of Tocilizumab in ASCT Following HD Melphalan Conditioning for Multiple Myeloma Patients
NCT05944783	PHASE4	NOT_YET_RECRUITING	Bioequivalence Studies of Dasatinib 100 Mg
NCT06057402	PHASE4	RECRUITING	Elranatamab Post Trial Access Study for Participants With Multiple Myeloma (MM)
NCT06251076	PHASE4	RECRUITING	Plan Development for Giving Teclistamab in the Outpatient Setting