Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T65864 Target Info
Target Name Stress-activated protein kinase 2a (p38 alpha)
Synonyms SAPK2A; P38 mitogen activatedprotein kinase; P38 Mitogen-activatedprotein kinase alpha; Mitogen-activated protein kinase p38 alpha; Mitogen-activated protein kinase 14; MXI2; MAX-interacting protein 2; MAPK 14; MAP kinase p38alpha; MAP kinase p38 alpha; MAP kinase MXI2; MAP kinase 14; Cytokine suppressive anti-inflammatory drug-binding protein; Cytokine suppressive anti-inflammatory drug binding protein; CSPB1; CSBP2; CSBP1; CSBP; CSAID-binding protein; CSAID binding protein; CRK1
Target Type Clinical trial Target
Gene Name MAPK14
Biochemical Class Kinase
UniProt ID
MK14_HUMAN
Ligand General Information  Top
Ligand Name VX-745 Ligand Info
Canonical SMILES C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl
InChI 1S/C19H9Cl2F2N3OS/c20-11-2-1-3-12(21)17(11)18-14-5-7-16(25-26(14)9-24-19(18)27)28-15-6-4-10(22)8-13(15)23/h1-9H
InChIKey VEPKQEUBKLEPRA-UHFFFAOYSA-N
PubChem Compound ID 3038525
Drug Binding Sites of Target  Top
PDB ID: 3HP5      Crystal Structure of Human p38alpha complexed with a pyrimidopyridazinone compound
Method X-ray diffraction Resolution 2.30 Å Mutation No [1]
PDB Sequence
PTFYRQELNK
15
TIWEVPERYQ
25
NLSPVGSVCA
40
AFDTKTGLRV
50
AVKKLSRPFQ
60

SIIHAKRTYR
70
ELRLLKHMKH
80
ENVIGLLDVF
90
TPARSLEEFN
100
DVYLVTHLMG
110

ADLNNIVKCQ
120
KLTDDHVQFL
130
IYQILRGLKY
140
IHSADIIHRD
150
LKPSNLAVNE
160

DCELKILDFG
170
VATRWYRAPE
192
IMLNWMHYNQ
202
TVDIWSVGCI
212
MAELLTGRTL
222

FPGTDHIDQL
232
KLILRLVGTP
242
GAELLKKISS
252
ESARNYIQSL
262
TQMPKMNFAN
272

VFIGANPLAV
282
DLLEKMLVLD
292
SDKRITAAQA
302
LAHAYFAQYH
312
DPDDEPVADP
322

YDQSFESRDL
332
LIDEWKSLTY
342
DEVISFVPPP
352
Residue
Distance (Å)
VAL30
3.942
VAL38
3.632
ALA51
3.284
VAL52
3.611
LYS53
3.503
GLU71
4.775
LEU75
3.975
ILE84
3.973
GLY85
4.409
LEU86
3.519
LEU104
3.256
VAL105
3.377
THR106
3.464
Residue
Distance (Å)
HIS107
3.815
LEU108
3.771
MET109
2.924
GLY110
2.612
ALA111
3.454
ASP112
3.592
ASN115
4.244
SER154
4.365
LEU156
4.775
ALA157
3.800
LEU167
3.652
ASP168
4.822
PDB ID: 3ZSI      X-ray structure of p38alpha bound to VX-745
Method X-ray diffraction Resolution 2.40 Å Mutation No [2]
PDB Sequence
PTFYRQELNK
15
TIWEVPERYQ
25
NLSPVGSGAY
35
GSVCAAFDTK
45
TGLRVAVKKL
55

SRPFQSIIHA
65
KRTYRELRLL
75
KHMKHENVIG
85
LLDVFTPARS
95
LEEFNDVYLV
105

THLMGADLNN
115
IKLTDDHVQF
129
LIYQILRGLK
139
YIHSADIIHR
149
DLKPSNLAVN
159

EDCELKILDF
169
GLTRWYRAPE
192
IMLNWMHYNQ
202
TVDIWSVGCI
212
MAELLTGRTL
222

FPGTDHIDQL
232
KLILRLVGTP
242
GAELLKKISS
252
ESARNYIQSL
262
KMNFANVFIG
276

ANPLAVDLLE
286
KMLVLDSDKR
296
ITAAQALAHA
306
YFAQYHDPDD
316
EPVADPYDQS
326

FESRDLLIDE
336
WKSLTYDEVI
346
SFVPPP
Residue
Distance (Å)
VAL30
3.537
VAL38
3.195
ALA51
3.372
VAL52
3.740
LYS53
3.472
GLU71
4.703
LEU75
3.663
ILE84
3.892
GLY85
4.463
LEU86
3.197
LEU104
3.272
VAL105
3.093
THR106
3.304
HIS107
3.878
Residue
Distance (Å)
LEU108
3.659
MET109
2.955
GLY110
2.714
ALA111
3.488
ASP112
3.408
ASN115
4.386
SER154
4.632
LEU156
4.852
ALA157
3.865
LEU167
3.445
ASP168
4.454
PHE169
3.909
GLY170
4.859
LEU171
3.956
PDB ID: 3FC1      Crystal structure of p38 kinase bound to pyrimido-pyridazinone inhibitor
Method X-ray diffraction Resolution 2.40 Å Mutation No [3]
PDB Sequence
RPTFYRQELN
14
IWEVPERYQN
26
LSPVGSVCAA
41
FDTKTGLRVA
51
VKKLSRPFQS
61

IIHAKRTYRE
71
LRLLKHMKHE
81
NVIGLLDVFT
91
PARSLEEFND
101
VYLVTHLMGA
111

DLNNIVKCQK
121
LTDDHVQFLI
131
YQILRGLKYI
141
HSADIIHRDL
151
KPSNLAVNED
161

CELKILDFGM
179
TGYVATRWYR
189
APEIMLNWMH
199
YNQTVDIWSV
209
GCIMAELLTG
219

RTLFPGTDHI
229
DQLKLILRLV
239
GTPGAELLKK
249
ISSESARNYI
259
QSLTQMPKMN
269

FANVFIGANP
279
LAVDLLEKML
289
VLDSDKRITA
299
AQALAHAYFA
309
QYHDPDDEPV
319

ADPYDQSFES
329
RDLLIDEWKS
339
LTYDEVISFV
349
PPPL
Residue
Distance (Å)
VAL30
3.981
VAL38
3.698
ALA51
3.339
VAL52
3.649
LYS53
3.358
LEU75
3.901
ILE84
3.927
GLY85
4.258
LEU86
3.340
LEU104
3.159
VAL105
3.237
THR106
3.443
Residue
Distance (Å)
HIS107
3.302
LEU108
3.098
MET109
2.803
GLY110
2.666
ALA111
3.710
ASP112
3.572
ASN115
4.206
SER154
4.219
LEU156
4.668
ALA157
3.921
LEU167
3.610
References  Top
REF 1 Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase. Bioorg Med Chem Lett. 2009 Oct 15;19(20):5851-6.
REF 2 X-ray structure of p38Alpha bound to TAK-715: comparison with three classic inhibitors. Acta Crystallogr D Biol Crystallogr. 2012 Aug;68(Pt 8):1041-50.
REF 3 Evaluating the molecular mechanics poisson-boltzmann surface area free energy method using a congeneric series of ligands to p38 MAP kinase. J Med Chem. 2005 Dec 1;48(24):7796-807.

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