Target Information
| Target General Information | Top | |||||
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| Target ID |
T94255
(Former ID: TTDI03595)
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| Target Name |
Long transient receptor potential channel 4 (TRPM4)
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| Synonyms |
hTRPM4; Transient receptor potential cation channel subfamily M member 4; Melastatin-4; LTrpC4; LTrpC-4; Calcium-activated non-selective cation channel 1
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| Gene Name |
TRPM4
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| Target Type |
Clinical trial target
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[1] | ||||
| Function |
Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.
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| BioChemical Class |
Transient receptor potential catioin channel
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| UniProt ID | ||||||
| Sequence |
MVVPEKEQSWIPKIFKKKTCTTFIVDSTDPGGTLCQCGRPRTAHPAVAMEDAFGAAVVTV
WDSDAHTTEKPTDAYGELDFTGAGRKHSNFLRLSDRTDPAAVYSLVTRTWGFRAPNLVVS VLGGSGGPVLQTWLQDLLRRGLVRAAQSTGAWIVTGGLHTGIGRHVGVAVRDHQMASTGG TKVVAMGVAPWGVVRNRDTLINPKGSFPARYRWRGDPEDGVQFPLDYNYSAFFLVDDGTH GCLGGENRFRLRLESYISQQKTGVGGTGIDIPVLLLLIDGDEKMLTRIENATQAQLPCLL VAGSGGAADCLAETLEDTLAPGSGGARQGEARDRIRRFFPKGDLEVLQAQVERIMTRKEL LTVYSSEDGSEEFETIVLKALVKACGSSEASAYLDELRLAVAWNRVDIAQSELFRGDIQW RSFHLEASLMDALLNDRPEFVRLLISHGLSLGHFLTPMRLAQLYSAAPSNSLIRNLLDQA SHSAGTKAPALKGGAAELRPPDVGHVLRMLLGKMCAPRYPSGGAWDPHPGQGFGESMYLL SDKATSPLSLDAGLGQAPWSDLLLWALLLNRAQMAMYFWEMGSNAVSSALGACLLLRVMA RLEPDAEEAARRKDLAFKFEGMGVDLFGECYRSSEVRAARLLLRRCPLWGDATCLQLAMQ ADARAFFAQDGVQSLLTQKWWGDMASTTPIWALVLAFFCPPLIYTRLITFRKSEEEPTRE ELEFDMDSVINGEGPVGTADPAEKTPLGVPRQSGRPGCCGGRCGGRRCLRRWFHFWGAPV TIFMGNVVSYLLFLLLFSRVLLVDFQPAPPGSLELLLYFWAFTLLCEELRQGLSGGGGSL ASGGPGPGHASLSQRLRLYLADSWNQCDLVALTCFLLGVGCRLTPGLYHLGRTVLCIDFM VFTVRLLHIFTVNKQLGPKIVIVSKMMKDVFFFLFFLGVWLVAYGVATEGLLRPRDSDFP SILRRVFYRPYLQIFGQIPQEDMDVALMEHSNCSSEPGFWAHPPGAQAGTCVSQYANWLV VLLLVIFLLVANILLVNLLIAMFSYTFGKVQGNSDLYWKAQRYRLIREFHSRPALAPPFI VISHLRLLLRQLCRRPRSPQPSSPALEHFRVYLSKEAERKLLTWESVHKENFLLARARDK RESDSERLKRTSQKVDLALKQLGHIREYEQRLKVLEREVQQCSRVLGWVAEALSRSALLP PGGPPPPDLPGSKD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| 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: Decavanadate | Ligand Info | |||||
| Structure Description | Cryo-EM structure of a human TRPM4 channel in complex with calcium and decavanadate | PDB:5WP6 | ||||
| Method | Electron microscopy | Resolution | 3.80 Å | Mutation | No | [7] |
| PDB Sequence |
EQSWIPKIFK
16 KKTCHTTEKP71 TDAYGELDFT81 GAGRKHSNFL91 RLSDRTDPAA101 VYSLVTRTWG 111 FRAPNLVVSV121 LGGSGGPVLQ131 TWLQDLLRRG141 LVRAAQSTGA151 WIVTGGLHTG 161 IGRHVGVAVR171 DHQMASTGGT181 KVVAMGVAPW191 GVVRNRDTLI201 NPKGSFPARY 211 RWRGVQFPLD226 YNYSAFFLVD236 DGTHGCLGGE246 NRFRLRLESY256 ISQQKTGVGG 266 TGIDIPVLLL276 LIDGDEKMLT286 RIENATQAQL296 PCLLVAGSGG306 AADCLAETLE 316 DTRQGEARDR334 IRRFFPKGDL344 EVLQAQVERI354 MTRKELLTVY364 SSEDGSEEFE 374 TIVLKALVKA384 CGSYLDELRL399 AVAWNRVDIA409 QSELFRGDIQ419 WRSFHLEASL 429 MDALLNDRPE439 FVRLLISHGL449 SLGHFLTPMR459 LAQLYSAAPS469 NSLIRNLLDQ 479 APWSDLLLWA566 LLLNRAQMAM576 YFWEMGSNAV586 SSALGACLLL596 RVMARLEPDA 606 EEAARRKDLA616 FKFEGMGVDL626 FGECYRSSEV636 RAARLLLRRC646 PLWGDATCLQ 656 LAMQADARAF666 FAQDGVQSLL676 TQKWWGDMAS686 TTPIWALVLA696 FFCPPLIYTR 706 LITFRRCLRR771 WFHFWGAPVT781 IFMGNVVSYL791 LFLLLFSRVL801 LVDFQPAPPG 811 SLELLLYFWA821 FTLLCEELRQ831 GLSGGSLASG843 GPGPGHASLS853 QRLRLYLADS 863 WNQCDLVALT873 CFLLGVGCRL883 TPGLYHLGRT893 VLCIDFMVFT903 VRLLHIFTVN 913 KQLGPKIVIV923 SKMMKDVFFF933 LFFLGVWLVA943 YGVATEGLLR953 PRDSDFPSIL 963 RRVFYRPYLQ973 IFGQIPQEDM983 DVALMEHSNC993 SSEPGFWAHP1003 PGAQAGTCVS 1013 QYANWLVVLL1023 LVIFLLVANI1033 LLVNLLIAMF1043 SYTFGKVQGN1053 SDLYWKAQRY 1063 RLIREFHSRP1073 ALAPPFIVIS1083 HLRLLLRQAL1106 EHFRVYLSKE1116 AERKLLTWES 1126 VHKENFLLAR1136 ARDKRESDSE1146 RLKRTSQKVD1156 LALKQLGHIR1166 EYEQRLKVLE 1176 REVQQCSRVL1186 GWVAEAL
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| Ligand Name: Cholesterol hemisuccinate | Ligand Info | |||||
| Structure Description | Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state | PDB:6BQV | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [8] |
| PDB Sequence |
TGAGRHSNFL
91 RLSDRTDPAA101 VYSLVTRTWG111 FRAPNLVVSV121 LGGSGGPVLQ131 TWLQDLLRRG 141 LVRAAQSTGA151 WIVTGGLHTG161 IGRHVGVAVR171 DHQMASTGGT181 KVVAMGVAPW 191 GVVRNRDTLI201 NPKGSFPARY211 RWVQFPLDYN228 YSAFFLVDDL243 GGENRFRLRL 253 ESYISQQKTG263 VGGTGIDIPV273 LLLLIDGDEK283 MLTRIENATQ293 AQLPCLLVAG 303 SGGAADCLAE313 TLEDTLGEAR332 DRIRRFFPKG342 DLEVLQAQVE352 RIMTRKELLT 362 VYSSEDGSEE372 FETIVLKALV382 KACGEASAYL394 DELRLAVAWN404 RVDIAQSELF 414 RGDIQWRSFH424 LEASLMDALL434 NDRPEFVRLL444 ISHGLSLGHF454 LTPMRLAQLY 464 SAAPSNSLIR474 NLLDQASVGH505 VLRMLLGPWS560 DLLLWALLLN570 RAQMAMYFWE 580 MGSNAVSSAL590 GACLLLRVMA600 RLEPDAEEAA610 RRKDLAFKFE620 GMGVDLFGEC 630 YRSSEVRAAR640 LLLRRCPLWG650 DATCLQLAMQ660 ADARAFFAQD670 GVQSLLTQKW 680 WGDMASTTPI690 WALVLAFFCP700 PLIYTRLITF710 RRCLRRWFHF775 WGAPVTIFMG 785 NVVSYLLFLL795 LFSRVLLVDF805 QPAPPGSLEL815 LLYFWAFTLL825 CEELRQGLSG 835 SGGPGPGHAS851 LSQRLRLYLA861 DSWNQCDLVA871 LTCFLLGVGC881 RLTPGLYHLG 891 RTVLCIDFMV901 FTVRLLHIFT911 VNKQLGPKIV921 IVSKMMKDVF931 FFLFFLGVWL 941 VAYGVATEGL951 LRPRDSDFPS961 ILRRVFYRPY971 LQIFGQIPQE981 DMDVALMEHS 991 NCSSEPGFWA1001 HPPGAQAGTC1011 VSQYANWLVV1021 LLLVIFLLVA1031 NILLVNLLIA 1041 MFSYTFGKVQ1051 GNSDLYWKAQ1061 RYRLIREFHS1071 RPALAPPFIV1081 ISHLRLLLRQ 1091 LCREHFRVYL1113 SKEAERKLLT1123 WESVHKENFL1133 LARARDKRES1143 DSERLKRTSQ 1153 KVDLALKQLG1163 HIREYEQRLK1173 VL
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TRP680
3.324
ILE690
3.678
LEU693
4.817
VAL694
3.642
PHE698
4.100
VAL780
4.018
PHE783
3.172
MET784
3.926
VAL787
3.748
VAL788
3.682
LEU791
3.380
LEU792
4.318
LEU795
3.649
TRP864
4.008
VAL904
4.245
LEU907
3.655
HIS908
3.590
PHE910
4.110
VAL912
4.500
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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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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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| Insulin secretion | hsa04911 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.50E-01 | Radiality | 1.20E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 6.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 14 |
| 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 | ||
| 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 | 9-phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels. Br J Pharmacol. 2008 Apr;153(8):1697-705. | |||||
| REF 3 | Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch. 2004 Apr;448(1):70-5. | |||||
| REF 4 | A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating transient receptor potential melastatin 4 ch... Mol Pharmacol. 2006 Apr;69(4):1413-20. | |||||
| REF 5 | Decavanadate modulates gating of TRPM4 cation channels. J Physiol. 2004 Nov 1;560(Pt 3):753-65. | |||||
| REF 6 | Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J Biol Chem. 2005 Nov 25;280(47):39185-92. | |||||
| REF 7 | Electron cryo-microscopy structure of a human TRPM4 channel. Nature. 2017 Dec 14;552(7684):200-204. | |||||
| REF 8 | Structure of the human TRPM4 ion channel in a lipid nanodisc. Science. 2018 Jan 12;359(6372):228-232. | |||||
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