Target Information
| Target General Information | Top | |||||
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| Target ID |
T64213
(Former ID: TTDR01160)
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| Target Name |
Transient receptor potential cation channel V4 (TRPV4)
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| Synonyms |
Vanilloid receptor-related osmotically-activated channel; Vanilloid receptor-like protein 2; Vanilloid receptor-like channel 2; VROAC; VRL2; VRL-2; VR-OAC; TrpV4; Transient receptor potential protein 12; Transient receptor potential cation channel subfamily V member 4; TRP12; Osm-9-like TRP channel 4; OTRPC4
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| Gene Name |
TRPV4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Heart failure [ICD-11: BD10-BD1Z] | |||||
| 3 | Hodgkin lymphoma [ICD-11: 2B30] | |||||
| Function |
Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by heat, low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8. Together with PKD2, forms mechano- and thermosensitive channels in cilium. Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to proinflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MADSSEGPRAGPGEVAELPGDESGTPGGEAFPLSSLANLFEGEDGSLSPSPADASRPAGP
GDGRPNLRMKFQGAFRKGVPNPIDLLESTLYESSVVPGPKKAPMDSLFDYGTYRHHSSDN KRWRKKIIEKQPQSPKAPAPQPPPILKVFNRPILFDIVSRGSTADLDGLLPFLLTHKKRL TDEEFREPSTGKTCLPKALLNLSNGRNDTIPVLLDIAERTGNMREFINSPFRDIYYRGQT ALHIAIERRCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPLSLAACTNQPHI VNYLTENPHKKADMRRQDSRGNTVLHALVAIADNTRENTKFVTKMYDLLLLKCARLFPDS NLEAVLNNDGLSPLMMAAKTGKIGIFQHIIRREVTDEDTRHLSRKFKDWAYGPVYSSLYD LSSLDTCGEEASVLEILVYNSKIENRHEMLAVEPINELLRDKWRKFGAVSFYINVVSYLC AMVIFTLTAYYQPLEGTPPYPYRTTVDYLRLAGEVITLFTGVLFFFTNIKDLFMKKCPGV NSLFIDGSFQLLYFIYSVLVIVSAALYLAGIEAYLAVMVFALVLGWMNALYFTRGLKLTG TYSIMIQKILFKDLFRFLLVYLLFMIGYASALVSLLNPCANMKVCNEDQTNCTVPTYPSC RDSETFSTFLLDLFKLTIGMGDLEMLSSTKYPVVFIILLVTYIILTFVLLLNMLIALMGE TVGQVSKESKHIWKLQWATTILDIERSFPVFLRKAFRSGEMVTVGKSSDGTPDRRWCFRV DEVNWSHWNQNLGIINEDPGKNETYQYYGFSHTVGRLRRDRWSSVVPRVVELNKNSNPDE VVVPLDSMGNPRCDGHQQGYPRKWRTDDAPL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T40EUL ; T97VA2 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | GSK2798745 | Drug Info | Phase 2 | Heart failure | [2], [3] | |
| 2 | phorbol 12-myristate 13-acetate | Drug Info | Phase 2 | Acute myeloid leukaemia | [4] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | GSK2798745 | Drug Info | [2], [3] | |||
| Activator | [+] 8 Activator drugs | + | ||||
| 1 | phorbol 12-myristate 13-acetate | Drug Info | [1] | |||
| 2 | 4alpha-PDD | Drug Info | [1] | |||
| 3 | 4alpha-PDH | Drug Info | [6] | |||
| 4 | 5,6-epoxyeicosatrienoic acid | Drug Info | [7] | |||
| 5 | bisandrographolide | Drug Info | [8] | |||
| 6 | citric acid | Drug Info | [10] | |||
| 7 | GSK1016790A | Drug Info | [11] | |||
| 8 | RN1747 | Drug Info | [14] | |||
| Inhibitor | [+] 5 Inhibitor drugs | + | ||||
| 1 | 4-Pyridin-2-yl-piperazine-1-carboxylic acid amide | Drug Info | [5] | |||
| 2 | 5'-iodoresiniferatoxin | Drug Info | [5] | |||
| 3 | CAPSAZEPINE | Drug Info | [9] | |||
| 4 | Pyrrolidin-1-yl-thiourea | Drug Info | [5] | |||
| 5 | SC-0030 | Drug Info | [15] | |||
| Blocker (channel blocker) | [+] 3 Blocker (channel blocker) drugs | + | ||||
| 1 | GSK2193874 | Drug Info | [12] | |||
| 2 | HC067047 | Drug Info | [13] | |||
| 3 | RN1734 | Drug Info | [14] | |||
| 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: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of the human TRPV4 ankyrin repeat domain | PDB:4DX2 | ||||
| Method | X-ray diffraction | Resolution | 2.95 Å | Mutation | No | [16] |
| PDB Sequence |
MFNRPILFDI
157 VSRGSTADLD167 GLLPFLLTHK177 KRLTDEEFRE187 PSTGKTCLPK197 ALLNLSNGRN 207 DTIPVLLDIA217 ERTGNMREFI227 NSPFRDIYYR237 GQTALHIAIE247 RRCKHYVELL 257 VAQGADVHAQ267 ARGRFFQPKD277 EGGYFYFGEL287 PLSLAACTNQ297 PHIVNYLTEN 307 PHKKADMRRQ317 DSRGNTVLHA327 LVAIADNTRE337 NTKFVTKMYD347 LLLLKCARLF 357 PDSNLEAVLN367 NDGLSPLMMA377 AKTGKIGIFQ387 HIIRREV
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| Ligand Name: Beta-D-Glucose | Ligand Info | |||||
| Structure Description | Crystal structure of the human TRPV4 ankyrin repeat domain | PDB:4DX2 | ||||
| Method | X-ray diffraction | Resolution | 2.95 Å | Mutation | No | [16] |
| PDB Sequence |
MFNRPILFDI
157 VSRGSTADLD167 GLLPFLLTHK177 KRLTDEEFRE187 PSTGKTCLPK197 ALLNLSNGRN 207 DTIPVLLDIA217 ERTGNMREFI227 NSPFRDIYYR237 GQTALHIAIE247 RRCKHYVELL 257 VAQGADVHAQ267 ARGRFFQPKD277 EGGYFYFGEL287 PLSLAACTNQ297 PHIVNYLTEN 307 PHKKADMRRQ317 DSRGNTVLHA327 LVAIADNTRE337 NTKFVTKMYD347 LLLLKCARLF 357 PDSNLEAVLN367 NDGLSPLMMA377 AKTGKIGIFQ387 HIIRREV
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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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There is no similarity protein (E value < 0.005) for this target
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cellular senescence | hsa04218 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Inflammatory mediator regulation of TRP channels | hsa04750 | Affiliated Target |
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| Class: Organismal Systems => Sensory system | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 1.70E-05 |
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| Closeness centrality | 1.77E-01 | Radiality | 1.29E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 6.00E+00 | Topological coefficient | 4.05E-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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Inflammatory mediator regulation of TRP channels | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | TRP channels | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem. 2002 Apr 19;277(16):13569-77. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands. Bioorg Med Chem Lett. 2004 Apr 5;14(7):1693-6. | |||||
| REF 6 | Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. J Med Chem. 2009 May 14;52(9):2933-9. | |||||
| REF 7 | Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003 Jul 24;424(6947):434-8. | |||||
| REF 8 | Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem. 2006 Oct 6;281(40):29897-904. | |||||
| REF 9 | Chain-branched acyclic phenethylthiocarbamates as vanilloid receptor antagonists. Bioorg Med Chem Lett. 2003 May 5;13(9):1549-52. | |||||
| REF 10 | Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 2003 Jun 20;278(25):22664-8. | |||||
| REF 11 | N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther. 2008 Aug;326(2):432-42. | |||||
| REF 12 | An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med. 2012 Nov 7;4(159):159ra148. | |||||
| REF 13 | Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19084-9. | |||||
| REF 14 | Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4. | |||||
| REF 15 | Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects. Bioorg Med Chem Lett. 2003 Dec 15;13(24):4389-93. | |||||
| REF 16 | Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. Biochemistry. 2012 Aug 7;51(31):6195-206. | |||||
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