Target Information
| Target General Information | Top | |||||
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| Target ID |
T28309
(Former ID: TTDI03598)
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| Target Name |
Mucolipin-1 (TRPML1)
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| Synonyms |
Transient receptor potential channel mucolipin 1; TRPML1; Mucolipidin; MSTP080; ML4; ML1; MG-2
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| Gene Name |
MCOLN1
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| Target Type |
Preclinical target
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[1] | ||||
| Function |
Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy. Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events. By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels. Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy. Functions as a Fe(2+) permeable channel in late endosomes and lysosomes. Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity).
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| UniProt ID | ||||||
| Sequence |
MTAPAGPRGSETERLLTPNPGYGTQAGPSPAPPTPPEEEDLRRRLKYFFMSPCDKFRAKG
RKPCKLMLQVVKILVVTVQLILFGLSNQLAVTFREENTIAFRHLFLLGYSDGADDTFAAY TREQLYQAIFHAVDQYLALPDVSLGRYAYVRGGGDPWTNGSGLALCQRYYHRGHVDPAND TFDIDPMVVTDCIQVDPPERPPPPPSDDLTLLESSSSYKNLTLKFHKLVNVTIHFRLKTI NLQSLINNEIPDCYTFSVLITFDNKAHSGRIPISLETQAHIQECKHPSVFQHGDNSFRLL FDVVVILTCSLSFLLCARSLLRGFLLQNEFVGFMWRQRGRVISLWERLEFVNGWYILLVT SDVLTISGTIMKIGIEAKNLASYDVCSILLGTSTLLVWVGVIRYLTFFHNYNILIATLRV ALPSVMRFCCCVAVIYLGYCFCGWIVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAM QAQQGRSSLVWLFSQLYLYSFISLFIYMVLSLFIALITGAYDTIKHPGGAGAEESELQAY IAQCQDSPTSGKFRRGSGSACSLLCCCGRDPSEEHSLLVN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | MK6-83 | Drug Info | Preclinical | Discovery agent | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | MK6-83 | Drug Info | [3] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | phosphatidyl (3,5) inositol biphosphate | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine | Ligand Info | |||||
| Structure Description | Structure of human TRPML1 with ML-SI3 | PDB:7MGL | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [4] |
| PDB Sequence |
DLRRRLKYFF
49 MSPCDKFRAK59 GRKPCKLMLQ69 VVKILVVTVQ79 LILFGLSNQL89 AVTFREENTI 99 AFRHLFLLGY109 SDGADDTFAA119 YTREQLYQAI129 FHAVDQYLAL139 PDVSLGRYAY 149 VRGGGDPWTN159 GSGLALCQRY169 YHRGHVDPAN179 DTFDIDPMVV189 TDCIQVDPPE 199 RSSYKNLTLK224 FHKLVNVTIH234 FRLKTINLQS244 LINNEIPDCY254 TFSVLITFDN 264 KAHSGRIPIS274 LETQAHIQEC284 KHPSVFQHGD294 NSFRLLFDVV304 VILTCSLSFL 314 LCARSLLRGF324 LLQNEFVGFM334 WRQRGRVISL344 WERLEFVNGW354 YILLVTSDVL 364 TISGTIMKIG374 IEAKNLASYD384 VCSILLGTST394 LLVWVGVIRY404 LTFFHNYNIL 414 IATLRVALPS424 VMRFCCCVAV434 IYLGYCFCGW444 IVLGPYHVKF454 RSLSMVSECL 464 FSLINGDDMF474 VTFAAMQAQQ484 GRSSLVWLFS494 QLYLYSFISL504 FIYMVLSLFI 514 ALITGAYDTI524 KH
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| Ligand Name: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide | Ligand Info | |||||
| Structure Description | Structure of human TRPML1 with ML-SI3 | PDB:7MGL | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [4] |
| PDB Sequence |
DLRRRLKYFF
49 MSPCDKFRAK59 GRKPCKLMLQ69 VVKILVVTVQ79 LILFGLSNQL89 AVTFREENTI 99 AFRHLFLLGY109 SDGADDTFAA119 YTREQLYQAI129 FHAVDQYLAL139 PDVSLGRYAY 149 VRGGGDPWTN159 GSGLALCQRY169 YHRGHVDPAN179 DTFDIDPMVV189 TDCIQVDPPE 199 RSSYKNLTLK224 FHKLVNVTIH234 FRLKTINLQS244 LINNEIPDCY254 TFSVLITFDN 264 KAHSGRIPIS274 LETQAHIQEC284 KHPSVFQHGD294 NSFRLLFDVV304 VILTCSLSFL 314 LCARSLLRGF324 LLQNEFVGFM334 WRQRGRVISL344 WERLEFVNGW354 YILLVTSDVL 364 TISGTIMKIG374 IEAKNLASYD384 VCSILLGTST394 LLVWVGVIRY404 LTFFHNYNIL 414 IATLRVALPS424 VMRFCCCVAV434 IYLGYCFCGW444 IVLGPYHVKF454 RSLSMVSECL 464 FSLINGDDMF474 VTFAAMQAQQ484 GRSSLVWLFS494 QLYLYSFISL504 FIYMVLSLFI 514 ALITGAYDTI524 KH
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.66E-01 | Radiality | 1.26E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 9.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 14 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome. Nat Commun. 2010 Jul 13;1:38. | |||||
| REF 2 | Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019 Dec;18(12):923-948. | |||||
| REF 3 | ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Res. 2020 Oct;182:104922. | |||||
| REF 4 | Atomic insights into ML-SI3 mediated human TRPML1 inhibition. Structure. 2021 Nov 4;29(11):1295-1302.e3. | |||||
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