Target Information
| Target General Information | Top | |||||
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| Target ID |
T00156
(Former ID: TTDI02490)
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| Target Name |
Short transient receptor potential channel 5 (TRPC5)
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| Synonyms |
hTRP5; hTRP-5; TrpC5; Transient receptor protein 5; TRP-5
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| Gene Name |
TRPC5
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Chronic kidney disease [ICD-11: GB61] | |||||
| 2 | Depression [ICD-11: 6A70-6A7Z] | |||||
| Function |
Thought to form a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Has also been shown to be calcium-selective. May also be activated by intracellular calcium store depletion.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MAQLYYKKVNYSPYRDRIPLQIVRAETELSAEEKAFLNAVEKGDYATVKQALQEAEIYYN
VNINCMDPLGRSALLIAIENENLEIMELLLNHSVYVGDALLYAIRKEVVGAVELLLSYRR PSGEKQVPTLMMDTQFSEFTPDITPIMLAAHTNNYEIIKLLVQKRVTIPRPHQIRCNCVE CVSSSEVDSLRHSRSRLNIYKALASPSLIALSSEDPILTAFRLGWELKELSKVENEFKAE YEELSQQCKLFAKDLLDQARSSRELEIILNHRDDHSEELDPQKYHDLAKLKVAIKYHQKE FVAQPNCQQLLATLWYDGFPGWRRKHWVVKLLTCMTIGFLFPMLSIAYLISPRSNLGLFI KKPFIKFICHTASYLTFLFMLLLASQHIVRTDLHVQGPPPTVVEWMILPWVLGFIWGEIK EMWDGGFTEYIHDWWNLMDFAMNSLYLATISLKIVAYVKYNGSRPREEWEMWHPTLIAEA LFAISNILSSLRLISLFTANSHLGPLQISLGRMLLDILKFLFIYCLVLLAFANGLNQLYF YYETRAIDEPNNCKGIRCEKQNNAFSTLFETLQSLFWSVFGLLNLYVTNVKARHEFTEFV GATMFGTYNVISLVVLLNMLIAMMNNSYQLIADHADIEWKFARTKLWMSYFDEGGTLPPP FNIIPSPKSFLYLGNWFNNTFCPKRDPDGRRRRRNLRSFTERNADSLIQNQHYQEVIRNL VKRYVAAMIRNSKTHEGLTEENFKELKQDISSFRYEVLDLLGNRKHPRSFSTSSTELSQR DDNNDGSGGARAKSKSVSFNLGCKKKTCHGPPLIRTMPRSSGAQGKSKAESSSKRSFMGP SLKKLGLLFSKFNGHMSEPSSEPMYTISDGIVQQHCMWQDIRYSQMEKGKAEACSQSEIN LSEVELGEVQGAAQSSECPLACSSSLHCASSICSSNSKLLDSSEDVFETWGEACDLLMHK WGDGQEEQVTTRL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T07TRP | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | BI 1358894 | Drug Info | Phase 2 | Depression | [2] | |
| 2 | GFB-887 | Drug Info | Phase 2 | Diabetic nephropathy | [3] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | BI 1358894 | Drug Info | [4] | |||
| 2 | GFB-887 | Drug Info | [5] | |||
| Agonist | [+] 1 Agonist drugs | + | ||||
| 1 | (-)-englerin A | Drug Info | [6] | |||
| Blocker (channel blocker) | [+] 5 Blocker (channel blocker) drugs | + | ||||
| 1 | 2-APB | Drug Info | [7] | |||
| 2 | bromoenol lactone | Drug Info | [8] | |||
| 3 | BTP2 | Drug Info | [9] | |||
| 4 | KB-R7943 | Drug Info | [10] | |||
| 5 | ML204 | Drug Info | [11] | |||
| Activator | [+] 2 Activator drugs | + | ||||
| 1 | daidzein | Drug Info | [9] | |||
| 2 | lysophosphatidylcholine | Drug Info | [9] | |||
| 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: Riluzole | Ligand Info | |||||
| Structure Description | Human TRPC5 channel in complex with riluzole | PDB:7WDB | ||||
| Method | Electron microscopy | Resolution | 2.40 Å | Mutation | No | [12] |
| PDB Sequence |
RIPLQIVRAE
26 TELSAEEKAF36 LNAVEKGDYA46 TVKQALQEAE56 IYYNVNINCM66 DPLGRSALLI 76 AIENENLEIM86 ELLLNHSVYV96 GDALLYAIRK106 EVVGAVELLL116 SYQFSEFTPD 142 ITPIMLAAHT152 NNYEIIKLLV162 QKRVTIPRPH172 QIRCNCVECV182 SSSEVDSLRH 192 SRSRLNIYKA202 LASPSLIALS212 SEDPILTAFR222 LGWELKELSK232 VENEFKAEYE 242 ELSQQCKLFA252 KDLLDQARSS262 RELEIILNHR272 DDLAKLKVAI294 KYHQKEFVAQ 304 PNCQQLLATL314 WYDGFPGWRR324 KHWVVKLLTC334 MTIGFLFPML344 SIAYLISPRS 354 NLGLFIKKPF364 IKFICHTASY374 LTFLFMLLLA384 SQHVQGPPPT401 VVEWMILPWV 411 LGFIWGEIKE421 MWDGGFTEYI431 HDWWNLMDFA441 MNSLYLATIS451 LKIVAYVKYN 461 GSRPREEWEM471 WHPTLIAEAL481 FAISNILSSL491 RLISLFTANS501 HLGPLQISLG 511 RMLLDILKFL521 FIYCLVLLAF531 ANGLNQLYFY541 YETRAIDEPN551 NCKGIRCEKQ 561 NNAFSTLFET571 LQSLFWSVFG581 LLNLYVTNVK591 ARHEFTEFVG601 ATMFGTYNVI 611 SLVVLLNMLI621 AMMNNSYQLI631 ADHADIEWKF641 ARTKLWMSYF651 DEGGTLPPPF 661 NIISLIQNQH712 YQEVIRNLVK722 RYVAAMIRNS732 KTTEENFKEL746 KQDISSFRYE 756 VLDLL
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| Ligand Name: Clemizole | Ligand Info | |||||
| Structure Description | Structure of human TRPC5 in complex with clemizole | PDB:7D4P | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | No | [13] |
| PDB Sequence |
RIPLQIVRAE
26 TELSAEEKAF36 LNAVEKGDYA46 TVKQALQEAE56 IYYNVNINCM66 DPLGRSALLI 76 AIENENLEIM86 ELLLNHSVYV96 GDALLYAIRK106 EVVGAVELLL116 SYTQFSEFTP 141 DITPIMLAAH151 TNNYEIIKLL161 VQKRVTIPRP171 HQIRCNCVEC181 VSSSEVDSLR 191 HSRSRLNIYK201 ALASPSLIAL211 SSEDPILTAF221 RLGWELKELS231 KVENEFKAEY 241 EELSQQCKLF251 AKDLLDQARS261 SRELEIILNH271 RDDLAKLKVA293 IKYHQKEFVA 303 QPNCQQLLAT313 LWYDGFPGWR323 RKHWVVKLLT333 CMTIGFLFPM343 LSIAYLISPR 353 SNLGLFIKKP363 FIKFICHTAS373 YLTFLFMLLL383 ASQDLHVQGP398 PPTVVEWMIL 408 PWVLGFIWGE418 IKEMWDGGFT428 EYIHDWWNLM438 DFAMNSLYLA448 TISLKIVAYV 458 KYNGSRPREE468 WEMWHPTLIA478 EALFAISNIL488 SSLRLISLFT498 ANSHLGPLQI 508 SLGRMLLDIL518 KFLFIYCLVL528 LAFANGLNQL538 YFYYETRAID548 EPNNCKGIRC 558 EKQNNAFSTL568 FETLQSLFWS578 VFGLLNLYVT588 NVKARHEFTE598 FVGATMFGTY 608 NVISLVVLLN618 MLIAMMNNSY628 QLIADHADIE638 WKFARTKLWM648 SYFDEGGTLP 658 PPFNIISLIQ709 NQHYQEVIRN719 LVKRYVAAMI729 RNSKTTEENF743 KELKQDISSF 753 RYEVLDLLG
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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).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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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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| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| GnRH secretion | hsa04929 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Affiliated Biological Pathways | Top | |||||
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| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Alzheimer disease-presenilin pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | TRP channels | |||||
| 2 | Role of second messengers in netrin-1 signaling | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Netrin-1 signaling | |||||
| References | Top | |||||
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| REF 1 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 2 | ClinicalTrials.gov (NCT04423757) A Home-based Study Using Mobile Technology to Test Whether BI 1358894 is Effective in People With Depression. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT04387448) A Phase 2a Multiple Ascending, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Diabetic Nephropathy, Focal Segmental Glomerulosclerosis, and Treatment-Resistant Minimal Change Disease. U.S.National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of Boehringer Ingelheim. | |||||
| REF 5 | Safety and Efficacy of GFB-887, a TRPC5 Channel Inhibitor, in Patients With Focal Segmental Glomerulosclerosis, Treatment-Resistant Minimal Change Disease, or Diabetic Nephropathy: TRACTION-2 Trial Design. Kidney Int Rep. 2021 Jul 23;6(10):2575-2584. | |||||
| REF 6 | (-)-Englerin is a potent and selective activator of TRPC4 and TRPC5 calcium channels. Angew Chem Int Ed Engl. 2015 Mar 16;54(12):3787-91. | |||||
| REF 7 | Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol. 2005 Jun;145(4):405-14. | |||||
| REF 8 | Bromoenol lactone inhibits voltage-gated Ca2+ and transient receptor potential canonical channels. J Pharmacol Exp Ther. 2011 Nov;339(2):329-40. | |||||
| REF 9 | 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: 490). | |||||
| REF 10 | The Na+/Ca2+ exchange inhibitor KB-R7943 potently blocks TRPC channels. Biochem Biophys Res Commun. 2007 Sep 14;361(1):230-6. | |||||
| REF 11 | Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem. 2011 Sep 23;286(38):33436-46. | |||||
| REF 12 | Structural identification of riluzole-binding site on human TRPC5. Cell Discov. 2022 Jul 12;8(1):67. | |||||
| REF 13 | Structural basis for human TRPC5 channel inhibition by two distinct inhibitors. Elife. 2021 Mar 8;10:e63429. | |||||
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