LONP1

Summary

LONP1 (lon peptidase 1, mitochondrial, HGNC:9479) is a protein-coding gene on chromosome 19p13.2, encoding Lon protease homolog, mitochondrial (P36776). ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix.

This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 9361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CODAS syndrome (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 1,164 total — 11 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 138
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004793

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9479
Approved symbol	LONP1
Name	lon peptidase 1, mitochondrial
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	LonHS, hLON, PIM1
Ensembl gene	ENSG00000196365
Ensembl biotype	protein_coding
OMIM	605490
Entrez	9361

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000360614, ENST00000540670, ENST00000585374, ENST00000586617, ENST00000587365, ENST00000587552, ENST00000588589, ENST00000589473, ENST00000590206, ENST00000590511, ENST00000590558, ENST00000590728, ENST00000590729, ENST00000591321, ENST00000593119, ENST00000877979, ENST00000877980, ENST00000913306, ENST00000958482

RefSeq mRNA: 3 — MANE Select: NM_004793 NM_001276479, NM_001276480, NM_004793

CCDS: CCDS12148, CCDS62507, CCDS62508

Canonical transcript exons

ENST00000360614 — 18 exons

Exon	Start	End
ENSE00001159037	5711771	5712002
ENSE00002927205	5719704	5720146
ENSE00003461937	5707060	5707143
ENSE00003477928	5691834	5692208
ENSE00003508105	5707697	5707826
ENSE00003515368	5694387	5694552
ENSE00003527974	5700789	5700927
ENSE00003548150	5696054	5696170
ENSE00003555354	5713134	5713253
ENSE00003568835	5693298	5693462
ENSE00003580175	5699027	5699205
ENSE00003589884	5705772	5705992
ENSE00003616601	5693552	5693769
ENSE00003642154	5696670	5696757
ENSE00003652842	5694761	5694901
ENSE00003671056	5708342	5708403
ENSE00003672230	5714183	5714271
ENSE00003674759	5696249	5696371

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.2543 / max 321.9639, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178559	42.5002	1820
178560	0.4984	258
178558	0.2557	110

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.86	gold quality
right adrenal gland cortex	UBERON:0035827	98.77	gold quality
left adrenal gland	UBERON:0001234	98.68	gold quality
left adrenal gland cortex	UBERON:0035825	98.49	gold quality
adrenal cortex	UBERON:0001235	98.47	gold quality
adrenal gland	UBERON:0002369	98.25	gold quality
apex of heart	UBERON:0002098	97.31	gold quality
adrenal tissue	UBERON:0018303	96.00	gold quality
stromal cell of endometrium	CL:0002255	95.98	gold quality
heart left ventricle	UBERON:0002084	95.32	gold quality
adenohypophysis	UBERON:0002196	95.10	gold quality
cardiac ventricle	UBERON:0002082	95.06	gold quality
right lobe of liver	UBERON:0001114	94.95	gold quality
pituitary gland	UBERON:0000007	94.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.65	gold quality
sural nerve	UBERON:0015488	94.59	gold quality
gastrocnemius	UBERON:0001388	94.53	gold quality
muscle of leg	UBERON:0001383	94.11	gold quality
anterior cingulate cortex	UBERON:0009835	94.09	gold quality
prefrontal cortex	UBERON:0000451	94.07	gold quality
right frontal lobe	UBERON:0002810	94.06	gold quality
cingulate cortex	UBERON:0003027	94.06	gold quality
right atrium auricular region	UBERON:0006631	93.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.71	gold quality
caudate nucleus	UBERON:0001873	93.66	gold quality
putamen	UBERON:0001874	93.63	gold quality
cerebellar hemisphere	UBERON:0002245	93.48	gold quality
nucleus accumbens	UBERON:0001882	93.45	gold quality
cerebellar cortex	UBERON:0002129	93.41	gold quality
heart	UBERON:0000948	93.27	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1, STAT3, STAT5A, STAT5B

miRNA regulators (miRDB)

1 targeting LONP1, 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-6791-5P	99.16	65.92	1844

Literature-anchored findings (GeneRIF, showing 40)

• may prevent extensive oxidation, aggregation and accumulation of aconitase, which could otherwise compromise mitochondrial function and cellular viability (PMID:12198491)
• Lon participates directly in the metabolism of mtDNA. (PMID:14739292)
• results indicate that mitochondrial Lon is required for normal survival and proliferation; a clear impetus for Lon’s evolutionary conservation (PMID:15683722)
• Results demonstrate that mitochondrial DNA binding is a physiological function of Lon and that cellular levels of Lon influence sensitivity to mtDNA damage. (PMID:17420247)
• Data show that Lon gene can be significantly downregulated by introduction of siRNA to result in enhanced sensitivity of MCF7 cells to UV, cisplatin and heat stress. (PMID:17584658)
• A review of the current knowledge on both catalytic mechanisms and inhibitors of Lon protease. (PMID:18021745)
• Electrophoretic mobility shift assay and circular dichroism show that ssDNAs with a propensity for forming parallel G-quartets are specifically bound by hLon. (PMID:18174225)
• We propose that decreased levels of mitochondrial proteases Lon and ClpP may allow heat shock protein 60 substrate proteins to go through more folding attempts (PMID:18378094)
• The promoter of Lon is at least part responsible for the upregulation of this protein during oxidative stress. (PMID:20933102)
• Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells. (PMID:21347624)
• Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. (PMID:21659532)
• In cells with normal mitochondrial DNA levels, phosphorylated TFAM is degraded by Lon. (PMID:23201127)
• Lon is overexpressed specifically in various types of cancer tissue including oral cancer. (PMID:23788038)
• Down-regulation of overexpressed human LON in cervical cancer suppresses cell proliferation and bioenergetics. (PMID:24260536)
• Lon protease deficiency led to an increase in ROS production and to an accumulation of carbonylated protein in the mitochondria. (PMID:24355201)
• Data indicate that SDH5 is protected from mitochondrial LON protease (LONM)-mediated degradation in mitochondria by its stable interaction with SDHA, a state that is dysregulated in hereditary paraganglioma 2 (PGL2). (PMID:24414418)
• StAR proteolysis is executed by at least 2 mitochondrial proteases, the matrix LON protease and the inner membrane complexes of the metalloproteases AFG3L2 and AFG3L2:SPG7/paraplegin. (PMID:24422629)
• Lonp1 has a protective role against ochratoxin a induced cytotoxicity in kidney cells. (PMID:24565693)
• Silencing of SIRT3 increased the levels of Lon protein and of its acetylation, suggesting that Lon is a target of SIRT3, likely at K917. (PMID:25128872)
• the structure of human mitochondrial Lon (hLon) protease, is reported. (PMID:25369343)
• We establish a link between LONP1 and CODAS syndrome in humans. (PMID:25574826)
• These results suggest that the mechanism underlying cell survival regulated by Lon is mediated by the maintenance of the protein stability of Hsp60-mtHsp70 complex. (PMID:25675302)
• LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix, and mutations in its ATP-binding and proteolytic domains cause CODAS syndrome. (PMID:25808063)
• Lon downregulation attenuated hypoxia-induced cardiomyocyte apoptosis through a reduction of reactive oxygen species level. (PMID:25922169)
• Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells. (PMID:26314956)
• A review on the recent discoveries concerning Lon Protease functions. [review] (PMID:26363553)
• This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. (PMID:26627475)
• Mutations of Lon, which likely impair its chaperone properties, are at the basis of a genetic inherited disease named the cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome. (Review) (PMID:27033304)
• Lon protease (Lonp1), which is a key inductive of mitochondrial unfolded protein response (UPR(mt)) and is required to maintain the mitochondrial quality, was greatly induced in H. pylori infected gastric epithelial cells. (PMID:27108387)
• LONP1 function and implication in human aging and disease was reviewed. (PMID:27387767)
• We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas. (PMID:27764809)
• Some features were not consistent with CODAS syndrome but overlapped with Marinesco-Sjogren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation (PMID:28148925)
• we observed that Lon protease downregulation is linked to a higher lipofuscinogenesis whereas the application of the mitochondrial-targeted antioxidant mitoTEMPO is able to prevent the accumulation of this protein aggregate. (PMID:28160744)
• Lon preferentially degrades the phosphorylated subunits of CcO and plays a role in the regulation of CcO activity in hypoxia and ischemia/reperfusion injury. (PMID:28442264)
• mitochondrial ATP-dependent Lon protease may serve as a potential biomarker for cancer diagnosis and novel target for the development of anticancer drugs and for predicting of the efficiency and effectiveness of chemotherapy of a variety of cancers. (PMID:29178076)
• This study shows that LONP1 mutations can cause infantile cataract with only partial or no apparent features of CODAS syndrome. Infantile cataract in the setting of ptosis, prominent columella, external ear abnormalities, lower extremity joint disease, or a combination of these features should raise suspicion for biallelic LONP1 mutations. (PMID:29408517)
• we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues. (PMID:29518248)
• The chaperone activity of Lon is important to bind with mitochondrial p53 by which increased Lon suppresses the apoptotic function of p53 under oxidative stress. (PMID:29899330)
• Investigated the role of LONP1 in mitochondrial proteostasis and gene expression. Depletion of LONP1 resulted in partial loss of mitochondrial DNA (mtDNA) and a complete suppression of mitochondrial translation associated with impaired ribosome biogenesis. (PMID:30061372)
• Mass spectrometry analysis revealed a similar substrate cleavage pattern between the bacterial and human Lon variants, which was exemplified by predominant representation of leucine, alanine, and other hydrophobic amino acids at the P(-1) site within the substrates. (PMID:30120231)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lonp1	ENSDARG00000102765
mus_musculus	Lonp1	ENSMUSG00000041168
rattus_norvegicus	Lonp1	ENSRNOG00000046502
drosophila_melanogaster	Lon	FBGN0036892
caenorhabditis_elegans	lonp-1	WBGENE00016391

Paralogs (1): LONP2 (ENSG00000102910)

Protein

Protein identifiers

Lon protease homolog, mitochondrial — P36776 (reviewed: P36776)

Alternative names: LONHs, Lon protease-like protein, Mitochondrial ATP-dependent protease Lon, Serine protease 15

All UniProt accessions (8): P36776, K7EJE8, K7EKE6, K7EQF8, K7ER27, K7ER56, K7ERR6, K7ERS1

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein, DELE1, helicase Twinkle (TWNK) and the large ribosomal subunit protein MRPL32/bL32m. MRPL32/bL32m is protected from degradation by LONP1 when it is bound to a nucleic acid (RNA), but TWNK is not. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single-stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site-specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters.

Subunit / interactions. Homohexamer. Organized in a ring with a central cavity. The ATP-binding and proteolytic domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. DNA and RNA binding is stimulated by substrate and inhibited by ATP binding. Interacts with TWNK and mitochondrial DNA polymerase subunit POLG.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Duodenum, heart, lung and liver, but not thymus.

Disease relevance. CODAS syndrome (CODASS) [MIM:600373] A rare syndrome characterized by the combination of cerebral, ocular, dental, auricular, and skeletal features. These include developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Peptidase activity is subject to substrate inhibition by ATP.

Domain organisation. The Lon N-terminal domains are crucial for the overall structure of the protein, maintaining it in a conformation allowing its proper functioning. The AP-domain (ATP-binding and proteolytic domains) has a closed-ring conformation in the presence of AMP-PNP and its N-terminal entry gate appears closed. Upon ADP binding, it switches to a lock-washer conformation and its N-terminal gate opens. The proteolytic site is connected to the ATP binding site through the GG loop (Gly-893 and Gly-894) and the loop containing Trp-770. Binding of a protein substrate such as beta-casein appears to trigger movement of both these loops as part of the conformational changes which lead to enhanced ATPase and peptidase activities.

Similarity. Belongs to the peptidase S16 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P36776-1	1	yes
P36776-2	2
P36776-3	3

RefSeq proteins (3): NP_001263408, NP_001263409, NP_004784* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003111	Lon_prtase_N	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR004815	Lon_bac/euk-typ	Family
IPR008268	Peptidase_S16_AS	Active_site
IPR008269	Lon_proteolytic	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR015947	PUA-like_sf	Homologous_superfamily
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027065	Lon_Prtase	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027503	Lonm_euk	Family
IPR046336	Lon_prtase_N_sf	Homologous_superfamily
IPR054594	Lon_lid	Domain

Pfam: PF00004, PF02190, PF05362, PF22667

Enzyme classification (BRENDA):

• EC 3.4.21.53 — Endopeptidase La (BRENDA: 68 organisms, 462 substrates, 175 inhibitors, 54 Km, 28 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.027–0.58	24
HUMAN TITIN	0.0022–0.053	5
HUMAN ALPHAA-CRYSTALLIN	0.035–0.05	2
HUMAN ALPHAB-CRYSTALLIN	0.026–0.058	2
IBPA	0.017–0.018	2
IBPB	0.016	2
ALPHA-CASEIN	0.026	1
BETA-GALACTOSIDASE FRAGMENT 3-93	0.073	1
BETA-GALACTOSIDASE-93-TITINI27	0.007	1
DIPHOSPHATE	0.15	1
F-QLRSLNGEWRFAWFPAPEAV-Q	0.0046	1
FRETN 89-98	1.027	1
QLRSLNGEWRFAWFPAPEAV	0.016	1
TITIN-I27CD	0.3	1
TITINI27-BETA-GALACTOSIDASE-93	0.015	1

UniProt features (120 total): helix 39, strand 30, sequence variant 15, mutagenesis site 9, sequence conflict 9, turn 4, compositionally biased region 3, active site 2, splice variant 2, domain 2, region of interest 2, transit peptide 1, chain 1, binding site 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
2X36	X-RAY DIFFRACTION	2
6X27	X-RAY DIFFRACTION	2.12
6WYS	X-RAY DIFFRACTION	2.23
6WZV	X-RAY DIFFRACTION	2.51
7P09	ELECTRON MICROSCOPY	2.7
7P0M	ELECTRON MICROSCOPY	2.75
8OJL	ELECTRON MICROSCOPY	2.88
9CC1	ELECTRON MICROSCOPY	2.92
7KRZ	ELECTRON MICROSCOPY	3.2
7KSM	ELECTRON MICROSCOPY	3.2
22IB	ELECTRON MICROSCOPY	3.22
9CC3	ELECTRON MICROSCOPY	3.23
9CC0	ELECTRON MICROSCOPY	3.31
7KSL	ELECTRON MICROSCOPY	3.5
6X1M	X-RAY DIFFRACTION	3.51
8OM7	ELECTRON MICROSCOPY	3.74
7NG5	ELECTRON MICROSCOPY	3.8
7NGL	ELECTRON MICROSCOPY	3.8
8OKA	ELECTRON MICROSCOPY	3.89
7NFY	ELECTRON MICROSCOPY	3.9
7OXO	ELECTRON MICROSCOPY	3.9
7P0B	ELECTRON MICROSCOPY	4.11
7NG4	ELECTRON MICROSCOPY	4.4
7NGF	ELECTRON MICROSCOPY	5.6
8OVF	ELECTRON MICROSCOPY	7.23
7NGC	ELECTRON MICROSCOPY	7.5
8OVG	ELECTRON MICROSCOPY	8.47
7NGQ	ELECTRON MICROSCOPY	12
7NGP	ELECTRON MICROSCOPY	15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36776-F1	77.35	0.33

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 (2): 898; 855

Ligand- & substrate-binding residues (1): 523–530

Mutagenesis-validated functional residues (9):

Position	Phenotype
529	abolishes atpase activity, and presumably atp-driven protein unfolding, but does not block access to the proteolytic act
770	has low basal, but normal stimulated atpase activity, and retains peptidase activity.
770	has normal basal, but low stimulated atpase activity, and abolishes peptidase activity.
855	lacks both atpase and protease activity, but retains dna binding activity.
880	enhances the basal, but not the stimulated atpase activity.
893	has low basal, but normal stimulated atpase activity, and retains peptidase activity.
893	has normal basal, but low stimulated atpase activity, and abolishes peptidase activity.
894	enhances the basal, but not the stimulated atpase activity, and retains peptidase activity.
894	enhances the basal, but not the stimulated atpase activity, and abolishes peptidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9841251	Mitochondrial unfolded protein response (UPRmt)
R-HSA-2262752	Cellular responses to stress
R-HSA-392499	Metabolism of proteins
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 1153 (showing top): VALK_AML_WITH_FLT3_ITD, GSE45365_NK_CELL_VS_CD11B_DC_DN, E2F_Q4, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, AP1_01, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, DORSAM_HOXA9_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, RORA1_01

GO Biological Process (16): response to hypoxia (GO:0001666), protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), mitochondrion organization (GO:0007005), response to hormone (GO:0009725), response to aluminum ion (GO:0010044), cellular response to oxidative stress (GO:0034599), mitochondrial protein catabolic process (GO:0035694), negative regulation of insulin receptor signaling pathway (GO:0046627), chaperone-mediated protein complex assembly (GO:0051131), obsolete proteolysis involved in protein catabolic process (GO:0051603), oxidation-dependent protein catabolic process (GO:0070407), obsolete mitochondrial genome maintenance (GO:0000002), proteolysis (GO:0006508), protein catabolic process (GO:0030163), mitochondrial DNA metabolic process (GO:0032042), protein-containing complex assembly (GO:0065003)

GO Molecular Function (19): single-stranded DNA binding (GO:0003697), single-stranded RNA binding (GO:0003727), ATP-dependent peptidase activity (GO:0004176), serine-type endopeptidase activity (GO:0004252), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), PH domain binding (GO:0042731), identical protein binding (GO:0042802), ADP binding (GO:0043531), insulin receptor substrate binding (GO:0043560), sequence-specific DNA binding (GO:0043565), G-quadruplex DNA binding (GO:0051880), DNA polymerase binding (GO:0070182), nucleotide binding (GO:0000166), DNA binding (GO:0003677), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), membrane (GO:0016020), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of proteins	1
Cellular responses to stress	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	4
DNA binding	3
cellular anatomical structure	3
protein catabolic process	2
protein metabolic process	2
peptidase activity	2
ATP-dependent activity	2
adenyl ribonucleotide binding	2
protein binding	2
cytoplasm	2
response to stress	1
response to decreased oxygen levels	1
organelle organization	1
response to endogenous stimulus	1
response to chemical	1
response to metal ion	1
response to oxidative stress	1
cellular response to chemical stress	1
mitochondrion organization	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
protein-containing complex assembly	1
modification-dependent protein catabolic process	1
macromolecule catabolic process	1
DNA metabolic process	1
cellular component assembly	1
protein-containing complex organization	1
RNA binding	1
endopeptidase activity	1
serine-type peptidase activity	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein domain specific binding	1
anion binding	1
enzyme binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1

Protein interactions and networks

STRING

3162 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LONP1	ACO2	Q99798	851
LONP1	CLPP	Q16740	845
LONP1	CRBN	Q96SW2	827
LONP1	HSPA9	P30036	796
LONP1	CLPX	O76031	770
LONP1	HSPD1	P10809	768
LONP1	PSMD5	Q16401	747
LONP1	YME1L1	Q96TA2	740
LONP1	HSPE1	P61604	714
LONP1	AFG3L2	Q9Y4W6	710
LONP1	SPG7	Q9UQ90	673
LONP1	ATF5	Q9Y2D1	655
LONP1	COX4I2	Q96KJ9	647
LONP1	OMA1	Q96E52	646
LONP1	TFAM	Q00059	627

IntAct

279 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
DCAF12L2	CETN3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
ANKRD17	HOXB6	psi-mi:“MI:0914”(association)	0.640
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
ACSF3	LONP1	psi-mi:“MI:0915”(physical association)	0.590
C1orf94	USO1	psi-mi:“MI:0914”(association)	0.550
SPMIP6	DCTN6	psi-mi:“MI:0914”(association)	0.530
KLHDC8A	PEX7	psi-mi:“MI:0914”(association)	0.530
MRPS24	ZZEF1	psi-mi:“MI:0914”(association)	0.530
RASL10B	AHCYL1	psi-mi:“MI:0914”(association)	0.530
DCAF4	CLUH	psi-mi:“MI:0914”(association)	0.530
GCAT	NDUFS6	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
MINK1	CNOT1	psi-mi:“MI:0914”(association)	0.530
GATA2	BANF1	psi-mi:“MI:0914”(association)	0.530
DCAF5	PFDN6	psi-mi:“MI:0914”(association)	0.530
TAF1C	DNAJA2	psi-mi:“MI:0914”(association)	0.530
NIPSNAP3A	CLUH	psi-mi:“MI:0914”(association)	0.530
PCK2	IGHA1	psi-mi:“MI:0914”(association)	0.530
KLHL33	HSPD1	psi-mi:“MI:0914”(association)	0.530
FBXO11	LONP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (589): LONP1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), CLPX (Co-fractionation), LONP1 (Co-fractionation), LONP1 (Co-fractionation), LONP1 (Co-fractionation), LONP1 (Co-fractionation), LONP1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), LONP1 (Proximity Label-MS), LONP1 (Proximity Label-MS), LONP1 (Proximity Label-MS), LONP1 (Proximity Label-MS)

ESM2 similar proteins: A0MTA1, A1YES6, A1YFZ3, A2T6Y4, A2T7I6, A3M208, A8J2Z9, A8XL25, B0V4U0, B0X4N8, B2I3E2, B7I5G4, O26314, O43049, P00388, P00389, P04175, P08967, P0A2X3, P0A2X4, P0C1I1, P13217, P23196, P26639, P26882, P27695, P28352, P36776, P37039, P37040, P37454, P43138, P51173, P93655, Q0UI56, Q16775, Q16T79, Q28333, Q388N2, Q3SYT8

Diamond homologs: A0L516, A0LG61, A0RJ87, A2QCJ2, A2YQ56, A4J7L6, A4S6Y4, A4XJL4, A5FG89, A6LD45, A7NM80, A8F811, A8HYF7, A8XFM8, A8ZX50, A9B3R2, A9GBF1, A9KH99, B0TFI9, B2KCC0, B2RII6, B2V6N0, B3E7K2, B3ERM8, B5EDX8, B5RL78, B5YFG2, B7FSL4, B8CY71, B8EMF2, B8G736, B8GX12, B8J198, O44952, O66605, O69177, O83536, O84348, P0A9M0, P0A9M1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
AKT1	“up-regulates activity”	LONP1	phosphorylation
LONP1	“down-regulates quantity by destabilization”	STAR	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 252 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
Mitochondrial translation	9	7.2×	3e-03
Mitochondrial translation initiation	9	6.6×	3e-03
Mitochondrial translation elongation	9	6.6×	3e-03
Mitochondrial ribosome-associated quality control	9	6.4×	3e-03
Regulation of PLK1 Activity at G2/M Transition	8	5.9×	8e-03
Mitochondrial translation termination	9	5.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial translation	9	7.1×	4e-03
protein autophosphorylation	10	6.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1164 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	15
Uncertain significance	383
Likely benign	514
Benign	87

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
180657	NM_004793.4(LONP1):c.2353A>G (p.Arg785Gly)	Pathogenic
180659	NM_004793.4(LONP1):c.1892C>A (p.Ser631Tyr)	Pathogenic
180660	NM_004793.4(LONP1):c.2171C>T (p.Ala724Val)	Pathogenic
2053784	NM_004793.4(LONP1):c.56_77dup (p.Gly28fs)	Pathogenic
2500194	NM_004793.4(LONP1):c.2154+1G>C	Pathogenic
2577993	NM_004793.4(LONP1):c.901C>G (p.Arg301Gly)	Pathogenic
3867646	NM_004793.4(LONP1):c.1391G>A (p.Trp464Ter)	Pathogenic
4711863	NM_004793.4(LONP1):c.2175C>A (p.Tyr725Ter)	Pathogenic
4819702	NM_004793.4(LONP1):c.1412dup (p.Lys472fs)	Pathogenic
818055	NM_004793.4(LONP1):c.798_804del (p.Pro267fs)	Pathogenic
997072	GRCh37/hg19 6p21.31-21.2(chr6:34401304-38435497)	Pathogenic
2498748	NM_004793.4(LONP1):c.901C>T (p.Arg301Trp)	Likely pathogenic
2500195	NM_004793.4(LONP1):c.917T>G (p.Leu306Trp)	Likely pathogenic
2632441	NM_004793.4(LONP1):c.1176dup (p.Lys393Ter)	Likely pathogenic
3000878	NM_004793.4(LONP1):c.2154+2T>C	Likely pathogenic
3374717	NM_004793.4(LONP1):c.2160dup (p.Arg721fs)	Likely pathogenic
3677172	NM_004793.4(LONP1):c.1072C>T (p.Arg358Trp)	Likely pathogenic
3775447	NM_004793.4(LONP1):c.1147dup	Likely pathogenic
383570	NM_004793.4(LONP1):c.2008G>T (p.Ala670Ser)	Likely pathogenic
4081494	NM_004793.4(LONP1):c.2087del (p.Leu696fs)	Likely pathogenic
423911	NM_004793.4(LONP1):c.161dup (p.Trp55fs)	Likely pathogenic
4686175	NM_004793.4(LONP1):c.1624C>T (p.Arg542Ter)	Likely pathogenic
504444	NM_004793.4(LONP1):c.2590_2615del (p.Leu864fs)	Likely pathogenic
523838	NM_004793.4(LONP1):c.859G>T (p.Glu287Ter)	Likely pathogenic
546340	NM_004793.4(LONP1):c.518+1G>A	Likely pathogenic
827778	NM_004793.4(LONP1):c.2815T>C (p.Tyr939His)	Likely pathogenic

SpliceAI

2695 predictions. Top by Δscore:

Variant	Effect	Δscore
19:5692208:CCTGG:C	acceptor_loss	1.0000
19:5693293:CTCA:C	donor_loss	1.0000
19:5693294:TCA:T	donor_loss	1.0000
19:5693295:CACCG:C	donor_loss	1.0000
19:5693296:A:AC	donor_gain	1.0000
19:5693296:A:T	donor_loss	1.0000
19:5693296:AC:A	donor_gain	1.0000
19:5693296:ACCG:A	donor_gain	1.0000
19:5693297:C:CC	donor_gain	1.0000
19:5693297:CC:C	donor_gain	1.0000
19:5693297:CCG:C	donor_gain	1.0000
19:5693297:CCGC:C	donor_gain	1.0000
19:5693297:CCGCA:C	donor_gain	1.0000
19:5693459:CGCC:C	acceptor_gain	1.0000
19:5693461:CC:C	acceptor_gain	1.0000
19:5693462:CC:C	acceptor_gain	1.0000
19:5693767:CTC:C	acceptor_gain	1.0000
19:5693769:CCTGA:C	acceptor_loss	1.0000
19:5693770:C:CC	acceptor_gain	1.0000
19:5694381:GCTCA:G	donor_loss	1.0000
19:5694382:CTCAC:C	donor_loss	1.0000
19:5694383:TCAC:T	donor_loss	1.0000
19:5694384:CAC:C	donor_loss	1.0000
19:5694385:A:AC	donor_gain	1.0000
19:5694385:AC:A	donor_gain	1.0000
19:5694385:ACCCA:A	donor_loss	1.0000
19:5694386:C:CC	donor_gain	1.0000
19:5694386:CC:C	donor_gain	1.0000
19:5694548:AACAC:A	acceptor_gain	1.0000
19:5694549:ACAC:A	acceptor_gain	1.0000

AlphaMissense

6235 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:5693436:G:C	S855R	1.000
19:5693436:G:T	S855R	1.000
19:5693438:T:G	S855R	1.000
19:5696061:A:T	I669N	1.000
19:5696112:C:G	R652P	1.000
19:5696147:G:C	N640K	1.000
19:5696147:G:T	N640K	1.000
19:5696284:C:G	D621H	1.000
19:5696313:A:G	L611P	1.000
19:5696316:A:G	L610P	1.000
19:5696322:A:G	L608P	1.000
19:5696325:A:G	L607P	1.000
19:5696670:C:A	E591D	1.000
19:5696670:C:G	E591D	1.000
19:5696671:T:A	E591V	1.000
19:5696672:C:T	E591K	1.000
19:5696674:T:A	D590V	1.000
19:5696675:C:G	D590H	1.000
19:5696680:A:G	L588P	1.000
19:5696731:C:T	G571E	1.000
19:5696732:C:A	G571W	1.000
19:5696734:G:T	P570H	1.000
19:5696740:G:T	A568D	1.000
19:5696741:C:G	A568P	1.000
19:5696743:C:T	G567D	1.000
19:5696744:C:G	G567R	1.000
19:5696750:A:C	Y565D	1.000
19:5696750:A:G	Y565H	1.000
19:5696755:C:G	R563P	1.000
19:5696757:C:A	R562S	1.000

dbSNP variants (sampled 300 via entrez): RS1000073927 (19:5698091 A>T), RS1000147140 (19:5702706 C>A,G,T), RS1000246957 (19:5721244 C>G,T), RS1000372469 (19:5704269 G>A), RS1000415889 (19:5719641 C>T), RS1000418305 (19:5692305 T>A,C), RS1000488039 (19:5719828 C>G,T), RS1000692097 (19:5712839 C>G,T), RS1000746251 (19:5718337 C>G,T), RS1000839975 (19:5701007 C>A,G,T), RS1000872736 (19:5701184 G>A), RS1000934162 (19:5700839 C>G), RS1000986578 (19:5707458 A>C,G), RS1001005843 (19:5692584 C>A), RS1001159971 (19:5691638 C>T)

Disease associations

OMIM: gene MIM:605490 | disease phenotypes: MIM:600373

GenCC curated gene-disease

Disease	Classification	Inheritance
CODAS syndrome	Strong	Autosomal recessive
pyruvate dehydrogenase E1-alpha deficiency	Supportive	X-linked
mitochondrial encephalomyopathy	Limited	Autosomal dominant
congenital diaphragmatic hernia	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (5): CODAS syndrome (MONDO:0010879), neurodevelopmental disorder (MONDO:0700092), mitochondrial encephalomyopathy (MONDO:0004675), congenital diaphragmatic hernia (MONDO:0005711), pyruvate dehydrogenase E1-alpha deficiency (MONDO:0010717)

Orphanet (1): CODAS syndrome (Orphanet:1458)

HPO phenotypes

138 total (30 of 138 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000072	Hydroureter
HP:0000143	Rectovaginal fistula
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth
HP:0000707	Abnormality of the nervous system
HP:0000776	Congenital diaphragmatic hernia
HP:0000884	Prominent sternum
HP:0000954	Single transverse palmar crease
HP:0001156	Brachydactyly
HP:0001216	Delayed ossification of carpal bones
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002481_11	Acne (severe)	2.000000e-06
GCST004602_106	Mean corpuscular volume	2.000000e-13
GCST004630_89	Mean corpuscular hemoglobin	1.000000e-14
GCST005790_69	Rosacea symptom severity	2.000000e-06
GCST008362_110	Birth weight	1.000000e-08
GCST010204_148	Low density lipoprotein cholesterol levels	5.000000e-11
GCST90002390_516	Mean corpuscular hemoglobin	3.000000e-09
GCST90002390_517	Mean corpuscular hemoglobin	3.000000e-20
GCST90002390_578	Mean corpuscular hemoglobin	7.000000e-46
GCST90002392_56	Mean corpuscular volume	1.000000e-23
GCST90002392_671	Mean corpuscular volume	2.000000e-46
GCST90002396_285	Mean reticulocyte volume	4.000000e-17
GCST90002397_130	Mean spheric corpuscular volume	4.000000e-23
GCST90002397_178	Mean spheric corpuscular volume	8.000000e-14
GCST90002403_147	Red blood cell count	1.000000e-11
GCST90002403_275	Red blood cell count	3.000000e-09
GCST90002404_255	Red cell distribution width	2.000000e-13
GCST90002404_554	Red cell distribution width	2.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0009180	rosacea severity measurement
EFO:0004344	birth weight
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D017237	Mitochondrial Encephalomyopathies	C05.651.460.620; C10.228.140.163.540; C10.668.491.500.500; C18.452.132.540; C18.452.660.560.620
D065886	Neurodevelopmental Disorders	F03.625
C536434	CODAS syndrome (supp.)
C564071	Pyruvate Dehydrogenase E1 Alpha Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879436 (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: 13,120 (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
CHEMBL325041	BORTEZOMIB	4	13,120

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — AAA ATPases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 12d [PMID: 33821636]	Inhibition	7.77	pIC50

Binding affinities (BindingDB)

16 measured of 46 human assays (46 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[(1R)-1-[[(2R)-3-methoxy-2-[[(2R)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-4-phenylbutyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-4-(3-chlorophenyl)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-2-(1,3-dioxoisoindol-2-yl)-3-methoxypropanoyl]amino]-4-phenylbutyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-4-(3-methoxyphenyl)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-2-cyclopropyl-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]ethyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-3-(4-chloro-2-methylphenoxy)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]propyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R,3S)-3-methoxy-2-(pyrazine-2-carbonylamino)butanoyl]amino]-3-phenoxypropyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]-3-methylbutyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-3-methoxy-2-[[(2R)-oxane-2-carbonyl]amino]propanoyl]amino]-4-phenylbutyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]-3-phenylpropyl]boronic acid	IC50	275 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-2-(2,5-dioxopyrrolidin-1-yl)-3-methoxypropanoyl]amino]-4-phenylbutyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1S)-3-(4-chloro-3-fluorophenoxy)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]propyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1S)-3-(4-chloro-2-fluorophenoxy)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]propyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-4-(4-hydroxyphenyl)-1-[[(2R)-3-hydroxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-4-(4-hydroxyphenyl)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS
[(1R)-1-[[(2R)-3-methoxy-2-(pyrazine-2-carbonylamino)propanoyl]amino]-4-oxo-4-phenylbutyl]boronic acid	IC50	2750 nM	US-20250320234: LONP1 INHIBITOR COMPOUNDS, USES AND METHODS

ChEMBL bioactivities

28 potent at pChembl≥5 of 28 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.77	IC50	17	nM	CHEMBL4876525
7.75	IC50	18	nM	CHEMBL4856865
7.47	IC50	34	nM	CHEMBL4864108
7.42	IC50	38	nM	CHEMBL4877126
7.23	IC50	59	nM	CHEMBL4870013
7.19	IC50	65	nM	CHEMBL4862424
7.19	Kd	64.39	nM	CHEMBL5653589
7.19	ED50	64.39	nM	CHEMBL5653589
7.11	IC50	77	nM	CHEMBL4870902
7.04	IC50	92	nM	CHEMBL4876920
7.04	IC50	92	nM	CHEMBL4850612
7.03	IC50	93	nM	CHEMBL4856768
6.96	IC50	109	nM	CHEMBL4847335
6.87	IC50	136	nM	CHEMBL4863384
6.86	IC50	137	nM	CHEMBL4847763
6.74	IC50	183	nM	BORTEZOMIB
6.73	IC50	187	nM	CHEMBL4861871
6.60	IC50	253	nM	CHEMBL4858320
6.39	IC50	408	nM	CHEMBL4853599
6.36	IC50	433	nM	CHEMBL4864045
6.26	IC50	546	nM	CHEMBL4859172
6.25	IC50	556	nM	CHEMBL4850826
6.24	Kd	575.2	nM	CHEMBL3752910
6.24	ED50	575.2	nM	CHEMBL3752910
5.68	IC50	2111	nM	CHEMBL524664
5.54	IC50	2850	nM	CHEMBL4862987
5.53	IC50	2980	nM	CHEMBL1530
5.21	IC50	6199	nM	CHEMBL4854436

PubChem BioAssay actives

26 with measured affinity, of 28 total; 26 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
[(1R)-4-phenyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0170	uM
[(1R)-4-phenyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0180	uM
[(1R)-3-phenyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]propyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0340	uM
[(1R)-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]pentyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0380	uM
[(1R)-1-[[(2R)-2-[(2,4-dimethyl-1,3-oxazole-5-carbonyl)amino]pentanoyl]amino]-4-phenylbutyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0590	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148660: Binding affinity to human LONP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0644	uM
[(1R)-5-methyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]hexyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0650	uM
[(1R)-6-bromo-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]hexyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0770	uM
[(1R)-2-cyclohexyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]ethyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0920	uM
[(1R)-3-phenyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]propyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0920	uM
[(1R)-3-methyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)hexanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.0930	uM
[(1R)-2-phenyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]ethyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.1090	uM
[(1R)-2-cyclohexyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]ethyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.1360	uM
[(1R)-1-[[(2R)-3-cyclohexyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]-3-methylbutyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.1370	uM
Bortezomib	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.1830	uM
[(1R)-3-methyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.1870	uM
[(1R)-3-methyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.2530	uM
[(1R)-3-methyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)butanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.4080	uM
[(1R)-3-methyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.4330	uM
[(1R)-3-methyl-1-[[(2R)-3-methyl-2-(pyrazine-2-carbonylamino)butanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.5460	uM
[(1R)-2-phenyl-1-[[(2R)-2-(pyrazine-2-carbonylamino)pentanoyl]amino]ethyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	0.5560	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148660: Binding affinity to human LONP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.5752	uM
[(1S)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	2.1110	uM
[(1R)-1-[[(2R)-3,3-dimethyl-2-(pyrazine-2-carbonylamino)butanoyl]amino]-3-methylbutyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	2.8500	uM
[(1S)-3-methyl-1-[[(2R)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	2.9800	uM
[(1R)-3-methyl-1-[[2-methyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid	1764782: Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	ic50	6.1990	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	5
Cyclosporine	increases expression, affects cotreatment	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Valproic Acid	affects expression, increases expression	3
ochratoxin A	affects reaction, decreases expression, decreases reaction	2
Acetaminophen	decreases expression, affects response to substance	2
Vehicle Emissions	decreases methylation, increases abundance, increases expression	2
Ivermectin	decreases expression, increases expression	2
Rotenone	decreases expression, increases expression	2
Tunicamycin	increases expression	2
Thapsigargin	increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
brilliant green	increases expression	1
lead acetate	affects reaction, increases abundance, increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
efavirenz	affects localization, increases expression, increases response to substance, decreases reaction	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4823871	Binding	Inhibition of LONP1 (unknown origin) using QXL520-YRGITCSGRQK(5-FAM)-NH2 peptide as substrate incubated for 50 mins in presence of ATP by HTRF assay	Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_BX21	GM25285	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
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,
NCT00257946	PHASE3	TERMINATED	Type of Material in Repair of Congenital Diaphragmatic Hernia
NCT03861182	PHASE3	TERMINATED	Contribution of PRF in CDH in Children With Prothetic Patch Closure
NCT06946576	PHASE3	NOT_YET_RECRUITING	Safety and Efficacy of Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
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
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT00373438	PHASE2	UNKNOWN	Fetoscopic Tracheal Balloon Occlusion in Left Diaphragmatic Hernia
NCT00966823	PHASE2	TERMINATED	Fetal Tracheal Balloon Study in Diaphragmatic Hernia
NCT01302977	PHASE2	UNKNOWN	Fetal Tracheal Occlusion in Severe Diaphragmatic Hernia: a Randomized Trial
NCT01731509	PHASE2	UNKNOWN	Early FETO for Severe Congenital Diaphragmatic Hernia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT05201144	PHASE2	RECRUITING	A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)
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
NCT03526588	PHASE1	TERMINATED	Umbilical Cord Blood Mononuclear Cells for Hypoxic Neurologic Injury in Infants With Congenital Diaphragmatic Hernia (CDH)
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
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06213090	Not specified	RECRUITING	Patterns of Neurodevelopmental Disorders
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT00371241	Not specified	COMPLETED	Antibody Secreting Cell and Cyotokine Profiles in Neonates on ECMO
NCT00373763	Not specified	WITHDRAWN	Fetoscopic Tracheal Balloon Occlusion in Unborns With Severe Congenital Diaphragmatic Hernia - EUROTRIAL I
NCT00763737	Not specified	COMPLETED	Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
NCT00881660	Not specified	COMPLETED	Fetal Endotracheal Occlusion (FETO) in Severe and Extremely Severe Congenital Diaphragmatic Hernia
NCT00950118	Not specified	RECRUITING	Diaphragmatic Hernia Research & Exploration, Advancing Molecular Science
NCT01098929	Not specified	UNKNOWN	Gene Mutations and Rescue in Human Congenital Diaphragmatic Hernia
NCT01155830	Not specified	COMPLETED	Inflammatory Cytokine Quantification in Infants