Target Information
| Target General Information | Top | |||||
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| Target ID |
T80165
(Former ID: TTDR00988)
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| Target Name |
Short transient receptor potential channel 6 (TRPC6)
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| Synonyms |
TRPC6; TRP6; STrpC6
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| Gene Name |
TRPC6
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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. Seems not to 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 |
MSQSPAFGPRRGSSPRGAAGAAARRNESQDYLLMDSELGEDGCPQAPLPCYGYYPCFRGS
DNRLAHRRQTVLREKGRRLANRGPAYMFSDRSTSLSIEEERFLDAAEYGNIPVVRKMLEE CHSLNVNCVDYMGQNALQLAVANEHLEITELLLKKENLSRVGDALLLAISKGYVRIVEAI LSHPAFAEGKRLATSPSQSELQQDDFYAYDEDGTRFSHDVTPIILAAHCQEYEIVHTLLR KGARIERPHDYFCKCNDCNQKQKHDSFSHSRSRINAYKGLASPAYLSLSSEDPVMTALEL SNELAVLANIEKEFKNDYKKLSMQCKDFVVGLLDLCRNTEEVEAILNGDVETLQSGDHGR PNLSRLKLAIKYEVKKFVAHPNCQQQLLSIWYENLSGLRQQTMAVKFLVVLAVAIGLPFL ALIYWFAPCSKMGKIMRGPFMKFVAHAASFTIFLGLLVMNAADRFEGTKLLPNETSTDNA KQLFRMKTSCFSWMEMLIISWVIGMIWAECKEIWTQGPKEYLFELWNMLDFGMLAIFAAS FIARFMAFWHASKAQSIIDANDTLKDLTKVTLGDNVKYYNLARIKWDPSDPQIISEGLYA IAVVLSFSRIAYILPANESFGPLQISLGRTVKDIFKFMVIFIMVFVAFMIGMFNLYSYYI GAKQNEAFTTVEESFKTLFWAIFGLSEVKSVVINYNHKFIENIGYVLYGVYNVTMVIVLL NMLIAMINSSFQEIEDDADVEWKFARAKLWFSYFEEGRTLPVPFNLVPSPKSLFYLLLKL KKWISELFQGHKKGFQEDAEMNKINEEKKLGILGSHEDLSKLSLDKKQVGHNKQPSIRSS EDFHLNSFNNPPRQYQKIMKRLIKRYVLQAQIDKESDEVNEGELKEIKQDISSLRYELLE EKSQNTEDLAELIRELGEKLSMEPNQEETNR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T32TBL | |||||
| 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: 4-[[(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-chlorobenzonitrile | Ligand Info | |||||
| Structure Description | Structure of SAR7334-bound TRPC6 at 2.9 angstrom | PDB:7DXG | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [4] |
| PDB Sequence |
LSIEEERFLD
104 AAEYGNIPVV114 RKMLEECHSL124 NVNCVDYMGQ134 NALQLAVANE144 HLEITELLLK 154 KENLSRVGDA164 LLLAISKGYV174 RIVEAILSHP184 AFAEGKRLDD205 FYAYDEDGTR 215 FSHDVTPIIL225 AAHCQEYEIV235 HTLLRKGARI245 ERPHDYFCKC255 NDCNQKQKHD 265 SFSHSRSRIN275 AYKGLASPAY285 LSLSSEDPVM295 TALELSNELA305 VLANIEKEFK 315 NDYKKLSMQC325 KDFVVGLLDL335 CRNTEEVEAI345 LNGDVETLQS355 GDHGRPNLSR 365 LKLAIKYEVK375 KFVAHPNCQQ385 QLLSIWYENL395 SGLRQQTMAV405 KFLVVLAVAI 415 GLPFLALIYW425 FAPCSKMGKI435 MRGPFMKFVA445 HAASFTIFLG455 LLVMNAADRF 465 EGTLFRMKTS489 CFSWMEMLII499 SWVIGMIWAE509 CKEIWTQGPK519 EYLFELWNML 529 DFGMLAIFAA539 SFIARFMAFW549 HASKAQSIID574 NVKYYNLARI584 KWDPSDPQII 594 SEGLYAIAVV604 LSFSRIAYIL614 PANESFGPLQ624 ISLGRTVKDI634 FKFMVIFIMV 644 FVAFMIGMFN654 LYSYYIGAKQ664 NEAFTTVEES674 FKTLFWAIFG684 LSEVKSVVIN 694 YNHKFIENIG704 YVLYGVYNVT714 MVIVLLNMLI724 AMINSSFQDA738 DVEWKFARAK 748 LWFSYFEEGR758 TLPVPFNLVP768 RQYQKIMKRL862 IKRYVLQAQI872 DKESDEVNEG 882 ELKEIKQDIS892 SLRYELLEEK902 SQNTEDLAEL912 IRELGEKL
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| Ligand Name: [(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl] octadec-10-enoate | Ligand Info | |||||
| Structure Description | Structure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in high calcium state | PDB:7DXF | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [4] |
| PDB Sequence |
LSIEEERFLD
104 AAEYGNIPVV114 RKMLEECHSL124 NVNCVDYMGQ134 NALQLAVANE144 HLEITELLLK 154 KENLSRVGDA164 LLLAISKGYV174 RIVEAILSHP184 AFAEGKRLDD205 FYAYDEDGTR 215 FSHDVTPIIL225 AAHCQEYEIV235 HTLLRKGARI245 ERPHDYFCKC255 NDCNQKQKHD 265 SFSHSRSRIN275 AYKGLASPAY285 LSLSSEDPVM295 TALELSNELA305 VLANIEKEFK 315 NDYKKLSMQC325 KDFVVGLLDL335 CRNTEEVEAI345 LNGDVETLQS355 GDHGRPNLSR 365 LKLAIKYEVK375 KFVAHPNCQQ385 QLLSIWYENL395 SGLRQQTMAV405 KFLVVLAVAI 415 GLPFLALIYW425 FAPCSKMGKI435 MRGPFMKFVA445 HAASFTIFLG455 LLVMNAADRF 465 EGTFRMKTSC490 FSWMEMLIIS500 WVIGMIWAEC510 KEIWTQGPKE520 YLFELWNMLD 530 FGMLAIFAAS540 FIARFMAFWH550 ASKAQSIIDN575 VKYYNLARIK585 WDPSDPQIIS 595 EGLYAIAVVL605 SFSRIAYILP615 ANESFGPLQI625 SLGRTVKDIF635 KFMVIFIMVF 645 VAFMIGMFNL655 YSYYIGAKQN665 EAFTTVEESF675 KTLFWAIFGL685 SEVKSVVINY 695 NHKFIENIGY705 VLYGVYNVTM715 VIVLLNMLIA725 MINSSFQEIE735 DDADVEWKFA 745 RAKLWFSYFE755 EGRTLPVPFN765 LVPRQYQKIM859 KRLIKRYVLQ869 AQIDKESDEV 879 NEGELKEIKQ889 DISSLRYELL899 EEKSQ
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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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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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| cGMP-PKG signaling pathway | hsa04022 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.85E-01 | Radiality | 1.31E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 1.05E+01 | Topological coefficient | 6.56E-01 | 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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| 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 | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | Endothelins | |||||
| 2 | Nephrin/Neph1 signaling in the kidney podocyte | |||||
| 3 | EPO signaling pathway | |||||
| 4 | PAR1-mediated thrombin signaling events | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Effects of PIP2 hydrolysis | |||||
| 2 | TRP channels | |||||
| 3 | Role of second messengers in netrin-1 signaling | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Primary Focal Segmental Glomerulosclerosis FSGS | |||||
| 2 | Platelet homeostasis | |||||
| 3 | Netrin-1 signaling | |||||
| 4 | GPCR downstream signaling | |||||
| 5 | Effects of PIP2 hydrolysis | |||||
| References | Top | |||||
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| REF 1 | Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature. 1999 Jan 21;397(6716):259-63. | |||||
| REF 2 | 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: 491). | |||||
| REF 3 | Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators--identification of a novel pharmacophore. Mol Pharmacol. 2010 Mar;77(3):368-77. | |||||
| REF 4 | 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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