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 T03046 Target Info
Target Name Mutated KRAS (mKRAS)
Synonyms c-Ki-ras (mutated); c-K-ras (mutated); RASK2 (mutated); Ki-Ras (mutated); KRAS2 (mutated); K-Ras 2 (mutated); GTPase KRas (mutated)
Target Type Clinical trial Target
Gene Name KRAS
UniProt ID
RASK_HUMAN
Ligand General Information  Top
Ligand Name 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol Ligand Info
Canonical SMILES C#CC1=C(C=CC2=CC(=CC(=C21)C3=NC=C4C(=C3F)N=C(N=C4N5CC6CCC(C5)N6)OCC78CCCN7CC(C8)F)O)F
InChI 1S/C33H31F3N6O2/c1-2-23-26(35)7-4-18-10-22(43)11-24(27(18)23)29-28(36)30-25(13-37-29)31(41-15-20-5-6-21(16-41)38-20)40-32(39-30)44-17-33-8-3-9-42(33)14-19(34)12-33/h1,4,7,10-11,13,19-21,38,43H,3,5-6,8-9,12,14-17H2/t19-,20-,21+,33+/m1/s1
InChIKey SCLLZBIBSFTLIN-INOGPEIASA-N
PubChem Compound ID 162369732
Drug Binding Sites of Target  Top
PDB ID: 7T47      KRAS G12D (GppCp) with MRTX-1133
Method X-ray diffraction Resolution 1.27 Å Mutation Yes [1]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

SLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLL
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKSDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEK
Residue
Distance (Å)
VAL9
3.416
GLY10
3.401
ALA11
4.303
ASP12
2.733
LYS16
4.642
THR58
4.530
ALA59
3.937
GLY60
2.781
GLN61
3.875
GLU62
3.005
GLU63
3.387
TYR64
3.089
SER65
3.921
Residue
Distance (Å)
ARG68
2.945
ASP69
2.680
MET72
3.627
PHE78
4.511
LYS88
4.035
ASP92
3.659
HIS95
2.880
TYR96
3.265
GLN99
3.477
ILE100
3.478
ARG102
3.816
VAL103
3.880
PDB ID: 7RPZ      KRAS G12D in complex with MRTX-1133
Method X-ray diffraction Resolution 1.30 Å Mutation Yes [2]
PDB Sequence
TEYKLVVVGA
11
DGVGKSALTI
21
QLIQNHFVDE
31
YDPTIEDSYR
41
KQVVIDGETS
51

LLDILDTAGQ
61
EEYSAMRDQY
71
MRTGEGFLLV
81
FAINNTKSFE
91
DIHHYREQIK
101

RVKDSEDVPM
111
VLVGNKSDLP
121
SRTVDTKQAQ
131
DLARSYGIPF
141
IETSAKTRQG
151

VDDAFYTLVR
161
EIRKHKEK
Residue
Distance (Å)
VAL9
3.446
GLY10
3.447
ALA11
4.340
ASP12
2.703
LYS16
4.681
THR58
4.452
ALA59
3.927
GLY60
2.794
GLN61
4.166
GLU62
2.847
GLU63
3.331
TYR64
3.264
SER65
4.121
Residue
Distance (Å)
ARG68
3.010
ASP69
2.630
MET72
3.599
PHE78
4.559
LYS88
4.140
ASP92
3.998
HIS95
2.833
TYR96
3.294
GLN99
3.460
ILE100
3.507
ARG102
3.756
VAL103
3.937
References  Top
REF 1 A Non-covalent KRASG12D Allele Specific Inhibitor Demonstrates Potent Inhibition of KRAS-dependent Signaling and Regression of KRASG12D-mutant Tumors. doi:10.21203/rs.3.rs-1261963/v1.
REF 2 Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133.

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