Target Information
| Target General Information | Top | |||||
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| Target ID |
T02546
(Former ID: TTDS00416)
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| Target Name |
Voltage-gated sodium channel alpha Nav1.4 (SCN4A)
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| Synonyms |
Voltage-gated sodium channel subunit alpha Nav1.4; Sodium channel protein type IV subunit alpha; Sodium channel protein skeletal muscle subunit alpha; SkM1; SCN4A
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| Gene Name |
SCN4A
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Musculoskeletal disorder [ICD-11: FA00-FC0Z] | |||||
| Function |
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle.
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| BioChemical Class |
Voltage-gated ion channel
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| UniProt ID | ||||||
| Sequence |
MARPSLCTLVPLGPECLRPFTRESLAAIEQRAVEEEARLQRNKQMEIEEPERKPRSDLEA
GKNLPMIYGDPPPEVIGIPLEDLDPYYSNKKTFIVLNKGKAIFRFSATPALYLLSPFSVV RRGAIKVLIHALFSMFIMITILTNCVFMTMSDPPPWSKNVEYTFTGIYTFESLIKILARG FCVDDFTFLRDPWNWLDFSVIMMAYLTEFVDLGNISALRTFRVLRALKTITVIPGLKTIV GALIQSVKKLSDVMILTVFCLSVFALVGLQLFMGNLRQKCVRWPPPFNDTNTTWYSNDTW YGNDTWYGNEMWYGNDSWYANDTWNSHASWATNDTFDWDAYISDEGNFYFLEGSNDALLC GNSSDAGHCPEGYECIKTGRNPNYGYTSYDTFSWAFLALFRLMTQDYWENLFQLTLRAAG KTYMIFFVVIIFLGSFYLINLILAVVAMAYAEQNEATLAEDKEKEEEFQQMLEKFKKHQE ELEKAKAAQALEGGEADGDPAHGKDCNGSLDTSQGEKGAPRQSSSGDSGISDAMEELEEA HQKCPPWWYKCAHKVLIWNCCAPWLKFKNIIHLIVMDPFVDLGITICIVLNTLFMAMEHY PMTEHFDNVLTVGNLVFTGIFTAEMVLKLIAMDPYEYFQQGWNIFDSIIVTLSLVELGLA NVQGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQ LFGKSYKECVCKIALDCNLPRWHMHDFFHSFLIVFRILCGEWIETMWDCMEVAGQAMCLT VFLMVMVIGNLVVLNLFLALLLSSFSADSLAASDEDGEMNNLQIAIGRIKLGIGFAKAFL LGLLHGKILSPKDIMLSLGEADGAGEAGEAGETAPEDEKKEPPEEDLKKDNHILNHMGLA DGPPSSLELDHLNFINNPYLTIQVPIASEESDLEMPTEEETDTFSEPEDSKKPPQPLYDG NSSVCSTADYKPPEEDPEEQAEENPEGEQPEECFTEACVQRWPCLYVDISQGRGKKWWTL RRACFKIVEHNWFETFIVFMILLSSGALAFEDIYIEQRRVIRTILEYADKVFTYIFIMEM LLKWVAYGFKVYFTNAWCWLDFLIVDVSIISLVANWLGYSELGPIKSLRTLRALRPLRAL SRFEGMRVVVNALLGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYYCINTTTSERFDI SEVNNKSECESLMHTGQVRWLNVKVNYDNVGLGYLSLLQVATFKGWMDIMYAAVDSREKE EQPQYEVNLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKLGGKDIFMTEEQKKYY NAMKKLGSKKPQKPIPRPQNKIQGMVYDLVTKQAFDITIMILICLNMVTMMVETDNQSQL KVDILYNINMIFIIIFTGECVLKMLALRQYYFTVGWNIFDFVVVILSIVGLALSDLIQKY FVSPTLFRVIRLARIGRVLRLIRGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYSIFG MSNFAYVKKESGIDDMFNFETFGNSIICLFEITTSAGWDGLLNPILNSGPPDCDPNLENP GTSVKGDCGNPSIGICFFCSYIIISFLIVVNMYIAIILENFNVATEESSEPLGEDDFEMF YETWEKFDPDATQFIAYSRLSDFVDTLQEPLRIAKPNKIKLITLDLPMVPGDKIHCLDIL FALTKEVLGDSGEMDALKQTMEEKFMAANPSKVSYEPITTTLKRKHEEVCAIKIQRAYRR HLLQRSMKQASYMYRHSHDGSGDDAPEKEGLLANTMSKMYGHENGNSSSPSPEEKGEAGD AGPTMGLMPISPSDTAWPPAPPPGQTVRPGVKESLV Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Lanperisone | Drug Info | Phase 3 | Musculoskeletal disorder | [1] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | SIPATRIGINE | Drug Info | Discontinued in Phase 2 | Neurological disorder | [2] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Lanperisone | Drug Info | [1] | |||
| 2 | XEP-018 | Drug Info | [8] | |||
| Inhibitor | [+] 13 Inhibitor drugs | + | ||||
| 1 | SIPATRIGINE | Drug Info | [3] | |||
| 2 | V-102862 | Drug Info | [4] | |||
| 3 | 3-(4-Phenoxy-phenyl)-1H-pyrazole | Drug Info | [4] | |||
| 4 | 3-[4-(4-Fluoro-phenoxy)-phenyl]-1H-pyrazole | Drug Info | [4] | |||
| 5 | BW-202W92 | Drug Info | [3] | |||
| 6 | CCACSSKWCRDHSRCC | Drug Info | [6] | |||
| 7 | CCNCASKWCRDHSRCC | Drug Info | [6] | |||
| 8 | CCNCSAKWCRDHSRCC | Drug Info | [6] | |||
| 9 | CCNCSSKWCRAHSRCC | Drug Info | [6] | |||
| 10 | CCNCSSKWCRDHARCC | Drug Info | [6] | |||
| 11 | CCNCSSKWCRDHSRCC | Drug Info | [6] | |||
| 12 | ZNCCNCSSKWCRDHSRCC | Drug Info | [6] | |||
| 13 | ZRCCNCSSKWCRDHSRCC | Drug Info | [6] | |||
| Activator | [+] 3 Activator drugs | + | ||||
| 1 | batrachotoxin | Drug Info | [5] | |||
| 2 | grayanotoxin III | Drug Info | [7] | |||
| 3 | veratridine | Drug Info | [5] | |||
| 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: (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en | Ligand Info | |||||
| Structure Description | Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1 | PDB:6AGF | ||||
| Method | Electron microscopy | Resolution | 3.20 Å | Mutation | No | [9] |
| PDB Sequence |
VVRRGAIKVL
128 IHALFSMFIM138 ITILTNCVFM148 TMSDPPPWSK158 NVEYTFTGIY168 TFESLIKILA 178 RGFCVDDFTF188 LRDPWNWLDF198 SVIMMAYLTE208 FVDLGNISAL218 RTFRVLRALK 228 TITVIPGLKT238 IVGALIQSVK248 KLSDVMILTV258 FCLSVFALVG268 LQLFMGNLRQ 278 KCVRWPPPFD337 WDAYISDEGN347 FYFLEGSNDA357 LLCGNSSDAG367 HCPEGYECIK 377 TGRNPNYGYT387 SYDTFSWAFL397 ALFRLMTQDY407 WENLFQLTLR417 AAGKTYMIFF 427 VVIIFLGSFY437 LINLILAVVA447 MAYAEQNEAT457 LAEDKENCCA562 PWLKFKNIIH 572 LIVMDPFVDL582 GITICIVLNT592 LFMAMEHYPM602 TEHFDNVLTV612 GNLVFTGIFT 622 AEMVLKLIAM632 DPYEYFQQGW642 NIFDSIIVTL652 SLVELGLANV662 QGLSVLRSFR 672 LLRVFKLAKS682 WPTLNMLIKI692 IGNSVGALGN702 LTLVLAIIVF712 IFAVVGMQLF 722 GKSYKECVCK732 IALDCNLPRW742 HMHDFFHSFL752 IVFRILCGEW762 IETMWDCMEV 772 AGQAMCLTVF782 LMVMVIGNLV792 VLNLFLALLL802 SSFSGKKWWT1019 LRRACFKIVE 1029 HNWFETFIVF1039 MILLSSGALA1049 FEDIYIEQRR1059 VIRTILEYAD1069 KVFTYIFIME 1079 MLLKWVAYGF1089 KVYFTNAWCW1099 LDFLIVDVSI1109 ISLVANWLGY1119 SELGPIKSLR 1129 TLRALRPLRA1139 LSRFEGMRVV1149 VNALLGAIPS1159 IMNVLLVCLI1169 FWLIFSIMGV 1179 NLFAGKFYYC1189 INTTTSERFD1199 ISEVNNKSEC1209 ESLMHTGQVR1219 WLNVKVNYDN 1229 VGLGYLSLLQ1239 VATFKGWMDI1249 MYAAVDSREK1259 EEQPQYEVNL1269 YMYLYFVIFI 1279 IFGSFFTLNL1289 FIGVIIDNFN1299 QQKKKLGGKD1309 IFMTEEQKKY1319 YNAMKKLGSK 1329 KPQKPIPRPQ1339 NKIQGMVYDL1349 VTKQAFDITI1359 MILICLNMVT1369 MMVETDNQSQ 1379 LKVDILYNIN1389 MIFIIIFTGE1399 CVLKMLALRQ1409 YYFTVGWNIF1419 DFVVVILSIV 1429 GLALSDLIQK1439 YFVSPTLFRV1449 IRLARIGRVL1459 RLIRGAKGIR1469 TLLFALMMSL 1479 PALFNIGLLL1489 FLVMFIYSIF1499 GMSNFAYVKK1509 ESGIDDMFNF1519 ETFGNSIICL 1529 FEITTSAGWD1539 GLLNPILNSG1549 PPDCDPNLEN1559 PGTSVKGDCG1569 NPSIGICFFC 1579 SYIIISFLIV1589 VNMYIAIILE1599 NFNVATEE
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| Ligand Name: 1-Hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine | Ligand Info | |||||
| Structure Description | Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1 | PDB:6AGF | ||||
| Method | Electron microscopy | Resolution | 3.20 Å | Mutation | No | [9] |
| PDB Sequence |
VVRRGAIKVL
128 IHALFSMFIM138 ITILTNCVFM148 TMSDPPPWSK158 NVEYTFTGIY168 TFESLIKILA 178 RGFCVDDFTF188 LRDPWNWLDF198 SVIMMAYLTE208 FVDLGNISAL218 RTFRVLRALK 228 TITVIPGLKT238 IVGALIQSVK248 KLSDVMILTV258 FCLSVFALVG268 LQLFMGNLRQ 278 KCVRWPPPFD337 WDAYISDEGN347 FYFLEGSNDA357 LLCGNSSDAG367 HCPEGYECIK 377 TGRNPNYGYT387 SYDTFSWAFL397 ALFRLMTQDY407 WENLFQLTLR417 AAGKTYMIFF 427 VVIIFLGSFY437 LINLILAVVA447 MAYAEQNEAT457 LAEDKENCCA562 PWLKFKNIIH 572 LIVMDPFVDL582 GITICIVLNT592 LFMAMEHYPM602 TEHFDNVLTV612 GNLVFTGIFT 622 AEMVLKLIAM632 DPYEYFQQGW642 NIFDSIIVTL652 SLVELGLANV662 QGLSVLRSFR 672 LLRVFKLAKS682 WPTLNMLIKI692 IGNSVGALGN702 LTLVLAIIVF712 IFAVVGMQLF 722 GKSYKECVCK732 IALDCNLPRW742 HMHDFFHSFL752 IVFRILCGEW762 IETMWDCMEV 772 AGQAMCLTVF782 LMVMVIGNLV792 VLNLFLALLL802 SSFSGKKWWT1019 LRRACFKIVE 1029 HNWFETFIVF1039 MILLSSGALA1049 FEDIYIEQRR1059 VIRTILEYAD1069 KVFTYIFIME 1079 MLLKWVAYGF1089 KVYFTNAWCW1099 LDFLIVDVSI1109 ISLVANWLGY1119 SELGPIKSLR 1129 TLRALRPLRA1139 LSRFEGMRVV1149 VNALLGAIPS1159 IMNVLLVCLI1169 FWLIFSIMGV 1179 NLFAGKFYYC1189 INTTTSERFD1199 ISEVNNKSEC1209 ESLMHTGQVR1219 WLNVKVNYDN 1229 VGLGYLSLLQ1239 VATFKGWMDI1249 MYAAVDSREK1259 EEQPQYEVNL1269 YMYLYFVIFI 1279 IFGSFFTLNL1289 FIGVIIDNFN1299 QQKKKLGGKD1309 IFMTEEQKKY1319 YNAMKKLGSK 1329 KPQKPIPRPQ1339 NKIQGMVYDL1349 VTKQAFDITI1359 MILICLNMVT1369 MMVETDNQSQ 1379 LKVDILYNIN1389 MIFIIIFTGE1399 CVLKMLALRQ1409 YYFTVGWNIF1419 DFVVVILSIV 1429 GLALSDLIQK1439 YFVSPTLFRV1449 IRLARIGRVL1459 RLIRGAKGIR1469 TLLFALMMSL 1479 PALFNIGLLL1489 FLVMFIYSIF1499 GMSNFAYVKK1509 ESGIDDMFNF1519 ETFGNSIICL 1529 FEITTSAGWD1539 GLLNPILNSG1549 PPDCDPNLEN1559 PGTSVKGDCG1569 NPSIGICFFC 1579 SYIIISFLIV1589 VNMYIAIILE1599 NFNVATEE
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LEU142
3.705
CYS145
3.898
VAL146
4.568
THR149
3.573
MET150
3.916
SER151
4.165
VAL247
3.783
LYS248
3.573
LEU250
3.501
SER251
3.660
MET254
3.683
ILE255
3.840
THR257
4.307
VAL258
4.625
LEU261
4.658
TYR384
3.713
GLY385
4.277
TYR386
4.091
SER393
3.521
TRP394
3.351
PHE396
3.680
LEU397
3.855
PHE400
3.911
MET403
3.895
THR404
4.143
GLN405
4.061
ILE439
3.979
ILE442
3.745
LEU443
3.779
SER696
3.770
THR704
3.369
LEU707
3.389
ALA708
4.257
ILE709
4.127
PHE712
3.749
ASP746
4.128
PHE747
4.254
PHE748
4.032
PHE751
3.964
PHE755
4.069
LEU758
4.282
CYS759
4.127
GLN775
3.424
ALA776
4.363
LEU779
4.279
THR780
3.920
LEU783
3.797
MET786
4.742
VAL787
3.961
ASN790
3.398
LEU791
3.775
VAL793
3.785
LEU794
3.624
LEU796
3.707
PHE797
4.215
ILE1160
3.825
VAL1163
4.378
LEU1164
3.722
CYS1167
3.616
LEU1168
4.445
TRP1171
4.058
ASN1229
4.971
GLY1231
3.279
LEU1232
3.374
TYR1234
4.036
LEU1235
4.093
LEU1238
4.255
ALA1241
3.643
THR1242
4.394
PHE1243
4.206
TYR1270
4.221
LEU1273
3.750
VAL1276
4.177
ILE1277
4.236
ILE1279
3.807
ILE1280
3.687
GLY1282
4.207
SER1283
3.969
PHE1284
4.079
PHE1285
4.028
THR1286
3.528
LEU1287
3.747
PHE1290
3.456
THR1533
4.941
THR1534
4.212
SER1535
4.303
SER1548
4.709
PRO1571
3.709
SER1572
2.904
ILE1575
4.129
CYS1576
3.696
CYS1579
4.104
SER1580
4.189
ILE1582
4.063
ILE1583
3.703
ILE1584
3.926
PHE1586
3.932
LEU1587
3.680
TYR1593
4.620
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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).
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
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Sodium/hydrogen exchanger 11 (SLC9C2) | 27.273 (36/132) | 6.26E-05 |
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.43E-01 | Radiality | 1.17E+01 | Clustering coefficient | 1.00E+00 |
| Neighborhood connectivity | 4.00E+00 | Topological coefficient | 8.00E-01 | 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 | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Interaction between L1 and Ankyrins | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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| REF 1 | Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels. J Pharmacol Exp Ther. 2005 Dec;315(3):1237-46. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003904) | |||||
| REF 3 | Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones. J Med Chem. 2009 May 14;52(9):2694-707. | |||||
| REF 4 | 3-(4-phenoxyphenyl)pyrazoles: a novel class of sodium channel blockers. J Med Chem. 2004 Mar 11;47(6):1547-52. | |||||
| REF 5 | Point mutations in segment I-S6 render voltage-gated Na+ channels resistant to batrachotoxin. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2653-8. | |||||
| REF 6 | Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels. J Biol Chem. 2007 Oct 19;282(42):30699-706. | |||||
| REF 7 | Novel site on sodium channel alpha-subunit responsible for the differential sensitivity of grayanotoxin in skeletal and cardiac muscle. Mol Pharmacol. 2001 Oct;60(4):865-72. | |||||
| REF 8 | 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: 581). | |||||
| REF 9 | Structure of the human voltage-gated sodium channel Na(v)1.4 in complex with beta1. Science. 2018 Oct 19;362(6412):eaau2486. | |||||
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