Target Information
| Target General Information | Top | |||||
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| Target ID |
T08133
(Former ID: TTDR00350)
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| Target Name |
Transient receptor potential cation channel V6 (TRPV6)
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| Synonyms |
Transient receptor potential cation channel subfamily V, member 6; TRPV6; HTRP8; ECaC2; Calcium transport protein CaT1; Calcium channel CAT1
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| Gene Name |
TRPV6
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Alzheimer disease [ICD-11: 8A20] | |||||
| 2 | Ovarian cancer [ICD-11: 2C73] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Calcium selective cation channel probably involved in Ca(2+) uptake in various tissues, including Ca(2+) reabsorption in intestine. The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification. Inactivation includes both, a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin- dependent mechanism, the lattermay be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MGPLQGDGGPALGGADVAPRLSPVRVWPRPQAPKEPALHPMGLSLPKEKGLILCLWSKFC
RWFQRRESWAQSRDEQNLLQQKRIWESPLLLAAKDNDVQALNKLLKYEDCKVHQRGAMGE TALHIAALYDNLEAAMVLMEAAPELVFEPMTSELYEGQTALHIAVVNQNMNLVRALLARR ASVSARATGTAFRRSPCNLIYFGEHPLSFAACVNSEEIVRLLIEHGADIRAQDSLGNTVL HILILQPNKTFACQMYNLLLSYDRHGDHLQPLDLVPNHQGLTPFKLAGVEGNTVMFQHLM QKRKHTQWTYGPLTSTLYDLTEIDSSGDEQSLLELIITTKKREARQILDQTPVKELVSLK WKRYGRPYFCMLGAIYLLYIICFTMCCIYRPLKPRTNNRTSPRDNTLLQQKLLQEAYMTP KDDIRLVGELVTVIGAIIILLVEVPDIFRMGVTRFFGQTILGGPFHVLIITYAFMVLVTM VMRLISASGEVVPMSFALVLGWCNVMYFARGFQMLGPFTIMIQKMIFGDLMRFCWLMAVV ILGFASAFYIIFQTEDPEELGHFYDYPMALFSTFELFLTIIDGPANYNVDLPFMYSITYA AFAIIATLLMLNLLIAMMGDTHWRVAHERDELWRAQIVATTVMLERKLPRCLWPRSGICG REYGLGDRWFLRVEDRQDLNRQRIQRYAQAFHTRGSEDLDKDSVEKLELGCPFSPHLSLP MPSVSRSTSRSSANWERLRQGTLRRDLRGIINRGLEDGESWEYQI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T09ICL | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | SOR-C13 | Drug Info | Phase 1 | Ovarian cancer | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | SOR-C13 | Drug Info | [1] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | 2-APB | Drug Info | [3] | |||
| 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: 2-APB | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoethoxydiphenyl borate (2-APB) | PDB:6D7T | ||||
| Method | Electron microscopy | Resolution | 4.44 Å | Mutation | Yes | [4] |
| PDB Sequence |
SWAQSRDEQN
37 LLQQKRIWES47 PLLLAAKDND57 VQALNKLLKY67 EDCKVHQRGA77 MGETALHIAA 87 LYDNLEAAMV97 LMEAAPELVF107 EPMTSELYEG117 QTALHIAVVN127 QNMNLVRALL 137 ARRASVSARA147 TGTAFRRSPC157 NLIYFGEHPL167 SFAACVNSEE177 IVRLLIEHGA 187 DIRAQDSLGN197 TVLHILILQP207 NKTFACQMYN217 LLLSYDRHGD227 HLQPLDLVPN 237 HQGLTPFKLA247 GVEGNTVMFQ257 HLMQKRKHTQ267 WTYGPLTSTL277 YDLTEIDSSG 287 DEQSLLELII297 TTKKREARQI307 LDQTPVKELV317 SLKWKRYGRP327 YFCMLGAIYL 337 LYIICFTMCC347 IYRPLKPRTN357 NRTSPRDNTL367 LQQKLLQEAY377 MTPKDDIRLV 387 GELVTVIGAI397 IILLVEVPDI407 FRMGVTRFFG417 QTILGGPFHV427 LIITYAFMVL 437 VTMVMRLISA447 SGEVVPMSFA457 LVLGWCNVMA467 FARGFQMLGP477 FTIMIQKMIF 487 GDLMRFCWLM497 AVVILGFASA507 FYIIFQTEDP517 EELGHFYDYP527 MALFSTFELF 537 LTIIDGPANY547 NVDLPFMYSI557 TYAAFAIIAT567 LLMLNLLIAM577 MGDTHWRVAH 587 ERDELWRAQI597 VATTVMLERK607 LPRCLWPRSG617 ICGREYGLGD627 RWFLRVEDRQ 637 D
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| Ligand Name: 1-[cis-4-(3-Methylphenyl)cyclohexyl]-4-(pyridin-3-yl)piperazine | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor cis-22a | PDB:7K4B | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [5] |
| PDB Sequence |
WFQRRESWAQ
31 SRDEQNLLQQ41 KRIWESPLLL51 AAKDNDVQAL61 NKLLKYEDCK71 VHQRGAMGET 81 ALHIAALYDN91 LEAAMVLMEA101 APELVFEPMT111 SELYEGQTAL121 HIAVVNQNMN 131 LVRALLARRA141 SVSARATGTA151 FRRSPCNLIY161 FGEHPLSFAA171 CVNSEEIVRL 181 LIEHGADIRA191 QDSLGNTVLH201 ILILQPNKTF211 ACQMYNLLLS221 YDRHGDHLQP 231 LDLVPNHQGL241 TPFKLAGVEG251 NTVMFQHLMQ261 KRKHTQWTYG271 PLTSTLYDLT 281 EIDSSGDEQS291 LLELIITTKK301 REARQILDQT311 PVKELVSLKW321 KRYGRPYFCM 331 LGAIYLLYII341 CFTMCCIYRP351 LKPRTNNRTS361 PRDNTLLQQK371 LLQEAYMTPK 381 DDIRLVGELV391 TVIGAIIILL401 VEVPDIFRMG411 VTPFHVLIIT431 YAFMVLVTMV 441 MRLISASGEV451 VPMSFALVLG461 WCNVMYFARG471 FQMLGPFTIM481 IQKMIFGDLM 491 RFCWLMAVVI501 LGFASAFYII511 FQTEDPEELG521 HFYDYPMALF531 STFELFLTII 541 DGPANYNVDL551 PFMYSITYAA561 FAIIATLLML571 NLLIAMMGDT581 HWRVAHERDE 591 LWRAQIVATT601 VMLERKLPRC611 LWPRSGICGR621 EYGLGDRWFL631 RVEDRQD |
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PRO424
3.706
PHE425
3.799
LEU428
4.268
SER455
4.567
PHE456
3.331
VAL459
3.504
LEU460
4.543
CYS463
4.183
MET466
3.719
THR479
3.720
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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 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 Pathway Affiliation
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Ankyrin repeat domain-containing protein 62 (ANKRD62) | 28.244 (37/131) | 3.22E-04 |
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Salivary secretion | hsa04970 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Mineral absorption | hsa04978 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.00E-01 | Radiality | 1.35E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 3.10E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Salivary secretion | |||||
| 2 | Mineral absorption | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | TCR signaling in naï | |||||
| 2 | ||||||
| 3 | Signaling events mediated by PTP1B | |||||
| 4 | TCR signaling in naï | |||||
| 5 | ||||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | TRP channels | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Vitamin D Receptor Pathway | |||||
| 2 | miR-targeted genes in lymphocytes - TarBase | |||||
| References | Top | |||||
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| REF 1 | In vivo detection of human TRPV6-rich tumors with anti-cancer peptides derived from soricidin. PLoS One. 2013;8(3):e58866. | |||||
| REF 2 | ClinicalTrials.gov (NCT01578564) Safety and Tolerability Study of SOR-C13 in Subjects With Advanced Cancers Commonly Known to Express the TRPV6 Channel. U.S. National Institutes of Health. | |||||
| REF 3 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 512). | |||||
| REF 4 | Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. Nat Commun. 2018 Jun 25;9(1):2465. | |||||
| REF 5 | Inactivation-mimicking block of the epithelial calcium channel TRPV6. Sci Adv. 2020 Nov 27;6(48):eabe1508. | |||||
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