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 T00749 Target Info
Target Name MEK kinase kinase 1 (MAP4K1)
Synonyms Mitogen-activated protein kinase kinase kinase kinase 1; MEKKK 1; MAPK/ERK kinase kinase kinase 1; Hematopoietic progenitor kinase; HPK1
Target Type Clinical trial Target
Gene Name MAP4K1
Biochemical Class Kinase
UniProt ID
M4K1_HUMAN
Ligand General Information  Top
Ligand Name N-{2-(3,3-difluoropyrrolidin-1-yl)-6-[(3R)-pyrrolidin-3-yl]pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine Ligand Info
Canonical SMILES CC(C)N1C2=CC(=NC=C2C=N1)NC3=NC(=NC(=C3)C4CCNC4)N5CCC(C5)(F)F
InChI 1S/C21H26F2N8/c1-13(2)31-17-8-18(25-10-15(17)11-26-31)28-19-7-16(14-3-5-24-9-14)27-20(29-19)30-6-4-21(22,23)12-30/h7-8,10-11,13-14,24H,3-6,9,12H2,1-2H3,(H,25,27,28,29)/t14-/m1/s1
InChIKey JKPAJCPZQIJPPS-CQSZACIVSA-N
PubChem Compound ID 135393494
Drug Binding Sites of Target  Top
PDB ID: 7R9N      Crystal structure of HPK1 in complex with GNE1858
Method X-ray diffraction Resolution 1.50 Å Mutation No [1]
PDB Sequence
VVDPDIFNRD
12
PRDHYDLLQR
22
LGGGTYGEVF
32
KARDKVSGDL
42
VALKMVKMEP
52

DDDVSTLQKE
62
ILILKTCRHA
72
NIVAYHGSYL
82
WLQKLWICME
92
FCGAGSLQDI
102

YQVTGSLSEL
112
QISYVCREVL
122
QGLAYLHSQK
132
KIHRDIKGAN
142
ILINDAGEVR
152

LADFGISAQI
162
GAELARRLEF
172
IGTPYWMAPE
182
VAAVALKGGY
192
NELCDIWSLG
202

ITAIELAELQ
212
PPLFDVHPLR
222
VLFLMTKSGY
232
QPPRLKEKGK
242
WSAAFHNFIK
252

VTLTKSPKKR
262
PSATKMLSHQ
272
LVSQPGLNRG
282
LILDLLDKLK
292
N
Residue
Distance (Å)
LEU23
3.318
GLY24
3.083
GLY25
4.322
TYR28
3.107
VAL31
3.436
ALA44
3.519
LYS46
4.116
VAL75
4.356
MET91
3.420
GLU92
3.085
Residue
Distance (Å)
PHE93
3.639
CYS94
2.922
GLY95
3.637
ALA96
3.682
GLY97
3.465
ASP101
3.966
LEU144
3.382
ALA154
4.265
ASP155
4.304
PDB ID: 6CQF      Crystal structure of HPK1 in complex an inhibitor G1858
Method X-ray diffraction Resolution 2.25 Å Mutation No [2]
PDB Sequence
PDIFNRDPRD
15
HYDLLQRLGG
25
GTYGEVFKAR
35
DKVSGDLVAL
45
KMVKMEPDDD
55

VSTLQKEILI
65
LKTCRHANIV
75
AYHGSYLWLQ
85
KLWICMEFCG
95
AGSLQDIYQV
105

TGSLSELQIS
115
YVCREVLQGL
125
AYLHSQKKIH
135
RDIKGANILI
145
NDAGEVRLAD
155

FGISAQIRLA
171
FIGTPYWMAP
181
EVAAVALKGG
191
YNELCDIWSL
201
GITAIELAEL
211

QPPLFDVHPL
221
RVLFLMTKSG
231
YQPPRLKEKG
241
KWSAAFHNFI
251
KVTLTKSPKK
261

RPSATKMLSH
271
QLVSQPGLNR
281
GLILDLLDKL
291
KN
Residue
Distance (Å)
LEU23
3.272
GLY24
3.299
GLY25
4.016
VAL31
3.654
ALA44
3.532
LYS46
4.191
VAL75
4.122
MET91
3.587
GLU92
3.317
PHE93
3.452
Residue
Distance (Å)
CYS94
2.823
GLY95
3.521
ALA96
3.826
GLY97
3.247
ASP101
3.256
ALA141
4.941
LEU144
3.376
ALA154
4.402
ASP155
4.950
References  Top
REF 1 Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1). ACS Med Chem Lett. 2021 Dec 8;13(1):84-91.
REF 2 Hematopoietic Progenitor Kinase-1 Structure in a Domain-Swapped Dimer. Structure. 2019 Jan 2;27(1):125-133.e4.

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