Target Information
| Target General Information | Top | |||||
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| Target ID |
T25861
(Former ID: TTDR00902)
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| Target Name |
Short transient receptor potential channel 3 (TRPC3)
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| Synonyms |
TrpC3; Htrp3; Htrp-3
Click to Show/Hide
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| Gene Name |
TRPC3
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| Target Type |
Literature-reported target
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[1] | ||||
| 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. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C, and by inositol 1,4,5- triphosphate receptors (ITPR) with bound IP3. May also be activated by internalcalcium store depletion.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MREKGRRQAVRGPAFMFNDRGTSLTAEEERFLDAAEYGNIPVVRKMLEESKTLNVNCVDY
MGQNALQLAVGNEHLEVTELLLKKENLARIGDALLLAISKGYVRIVEAILNHPGFAASKR LTLSPCEQELQDDDFYAYDEDGTRFSPDITPIILAAHCQKYEVVHMLLMKGARIERPHDY FCKCGDCMEKQRHDSFSHSRSRINAYKGLASPAYLSLSSEDPVLTALELSNELAKLANIE KEFKNDYRKLSMQCKDFVVGVLDLCRDSEEVEAILNGDLESAEPLEVHRHKASLSRVKLA IKYEVKKFVAHPNCQQQLLTIWYENLSGLREQTIAIKCLVVLVVALGLPFLAIGYWIAPC SRLGKILRSPFMKFVAHAASFIIFLGLLVFNASDRFEGITTLPNITVTDYPKQIFRVKTT QFTWTEMLIMVWVLGMMWSECKELWLEGPREYILQLWNVLDFGMLSIFIAAFTARFLAFL QATKAQQYVDSYVQESDLSEVTLPPEIQYFTYARDKWLPSDPQIISEGLYAIAVVLSFSR IAYILPANESFGPLQISLGRTVKDIFKFMVLFIMVFFAFMIGMFILYSYYLGAKVNAAFT TVEESFKTLFWSIFGLSEVTSVVLKYDHKFIENIGYVLYGIYNVTMVVVLLNMLIAMINS SYQEIEDDSDVEWKFARSKLWLSYFDDGKTLPPPFSLVPSPKSFVYFIMRIVNFPKCRRR RLQKDIEMGMGNSKSRLNLFTQSNSRVFESHSFNSILNQPTRYQQIMKRLIKRYVLKAQV DKENDEVNEGELKEIKQDISSLRYELLEDKSQATEELAILIHKLSEKLNPSMLRCE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T37DRC | |||||
| 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: Cholesterol hemisuccinate | Ligand Info | |||||
| Structure Description | Structure of TRPC3 at 2.7 angstrom in high calcium state | PDB:7DXB | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | No | [6] |
| PDB Sequence |
GPAFMFNTSL
24 TAEEERFLDA34 AEYGNIPVVR44 KMLEESKTLN54 VNCVDYMGQN64 ALQLAVGNEH 74 LEVTELLLKK84 ENLARIGDAL94 LLAISKGYVR104 IVEAILNHPG114 FAASKRLTLS 124 PCEQELQDDD134 FYAYDEDGTR144 FSPDITPIIL154 AAHCQKYEVV164 HMLLMKGARI 174 ERPHDYFCKC184 GDCMEKQRHD194 SFSHSRSRIN204 AYKGLASPAY214 LSLSSEDPVL 224 TALELSNELA234 KLANIEKEFK244 NDYRKLSMQC254 KDFVVGVLDL264 CRDSEEVEAI 274 LNGDASLSRV297 KLAIKYEVKK307 FVAHPNCQQQ317 LLTIWYENLS327 GLREQTIAIK 337 CLVVLVVALG347 LPFLAIGYWI357 APCSRLGKIL367 RSPFMKFVAH377 AASFIIFLGL 387 LVFNASDRFE397 GITTLPNITV407 TDYPKQIFRV417 KTTQFTWTEM427 LIMVWVLGMM 437 WSECKELWLE447 GPREYILQLW457 NVLDFGMLSI467 FIAAFTARFL477 AFLQATKAQQ 487 YVDSYVQESD497 LSEVTLPPEI507 QYFTYARDKW517 LPSDPQIISE527 GLYAIAVVLS 537 FSRIAYILPA547 NESFGPLQIS557 LGRTVKDIFK567 FMVLFIMVFF577 AFMIGMFILY 587 SYYLGAKVNA597 AFTTVEESFK607 TLFWSIFGLS617 EVTSVVLKYD627 HKFIENIGYV 637 LYGIYNVTMV647 VVLLNMLIAM657 INSSYQEIED667 DSDVEWKFAR677 SKLWLSYFDD 687 GKTLPPPFSL697 VPQPTRYQQI766 MKRLIKRYVL776 KAQVDKENDE786 VNEGELKEIK 796 QDISSLRYEL806 LEDKSQATEE816 LAILIHKL
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TRP322
3.952
TYR323
2.864
ILE334
4.771
LYS337
3.493
CYS338
4.952
VAL341
3.647
PHE371
3.225
PHE374
3.983
ALA378
4.703
ILE382
3.543
MET437
3.713
PHE462
4.438
SER466
4.844
ILE469
4.007
ALA470
3.599
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate | Ligand Info | |||||
| Structure Description | Structure of TRPC3 at 2.7 angstrom in high calcium state | PDB:7DXB | ||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | No | [6] |
| PDB Sequence |
GPAFMFNTSL
24 TAEEERFLDA34 AEYGNIPVVR44 KMLEESKTLN54 VNCVDYMGQN64 ALQLAVGNEH 74 LEVTELLLKK84 ENLARIGDAL94 LLAISKGYVR104 IVEAILNHPG114 FAASKRLTLS 124 PCEQELQDDD134 FYAYDEDGTR144 FSPDITPIIL154 AAHCQKYEVV164 HMLLMKGARI 174 ERPHDYFCKC184 GDCMEKQRHD194 SFSHSRSRIN204 AYKGLASPAY214 LSLSSEDPVL 224 TALELSNELA234 KLANIEKEFK244 NDYRKLSMQC254 KDFVVGVLDL264 CRDSEEVEAI 274 LNGDASLSRV297 KLAIKYEVKK307 FVAHPNCQQQ317 LLTIWYENLS327 GLREQTIAIK 337 CLVVLVVALG347 LPFLAIGYWI357 APCSRLGKIL367 RSPFMKFVAH377 AASFIIFLGL 387 LVFNASDRFE397 GITTLPNITV407 TDYPKQIFRV417 KTTQFTWTEM427 LIMVWVLGMM 437 WSECKELWLE447 GPREYILQLW457 NVLDFGMLSI467 FIAAFTARFL477 AFLQATKAQQ 487 YVDSYVQESD497 LSEVTLPPEI507 QYFTYARDKW517 LPSDPQIISE527 GLYAIAVVLS 537 FSRIAYILPA547 NESFGPLQIS557 LGRTVKDIFK567 FMVLFIMVFF577 AFMIGMFILY 587 SYYLGAKVNA597 AFTTVEESFK607 TLFWSIFGLS617 EVTSVVLKYD627 HKFIENIGYV 637 LYGIYNVTMV647 VVLLNMLIAM657 INSSYQEIED667 DSDVEWKFAR677 SKLWLSYFDD 687 GKTLPPPFSL697 VPQPTRYQQI766 MKRLIKRYVL776 KAQVDKENDE786 VNEGELKEIK 796 QDISSLRYEL806 LEDKSQATEE816 LAILIHKL
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Polycystic kidney disease 2-like 1 (TRPP2) | 23.077 (78/338) | 8.93E-08 | |
| Polycystin-2 (PKD2) | 27.632 (42/152) | 4.58E-07 |
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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 | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.12E-04 |
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| Closeness centrality | 2.06E-01 | Radiality | 1.36E+01 | Clustering coefficient | 1.67E-01 |
| Neighborhood connectivity | 2.10E+01 | Topological coefficient | 2.81E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Trk receptor signaling mediated by PI3K and PLC-gamma | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Effects of PIP2 hydrolysis | |||||
| 2 | TRP channels | |||||
| 3 | Role of second messengers in netrin-1 signaling | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Platelet homeostasis | |||||
| 2 | Netrin-1 signaling | |||||
| 3 | GPCR downstream signaling | |||||
| 4 | Effects of PIP2 hydrolysis | |||||
| References | Top | |||||
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| REF 1 | 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: 488). | |||||
| REF 2 | Mechanism of inhibition of TRPC cation channels by 2-aminoethoxydiphenylborane. Mol Pharmacol. 2005 Sep;68(3):758-62. | |||||
| REF 3 | A functional link between store-operated and TRPC channels revealed by the 3,5-bis(trifluoromethyl)pyrazole derivative, BTP2. J Biol Chem. 2005 Mar 25;280(12):10997-1006. | |||||
| REF 4 | Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999 Jan 21;397(6716):259-63. | |||||
| REF 5 | Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5400-5. | |||||
| REF 6 | Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites. Neuron. 2022 Mar 16;110(6):1023-1035.e5. | |||||
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