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 T48598 Target Info
Target Name GTPase KRas (KRAS)
Synonyms c-Ki-ras; c-K-ras; RASK2; Ki-Ras; KRAS2; K-Ras 2
Target Type Clinical trial Target
Gene Name KRAS
Biochemical Class Small GTPase
UniProt ID
RASK_HUMAN
Ligand General Information  Top
Ligand Name Phosphomethylphosphonic Acid Guanylate Ester Ligand Info
Canonical SMILES C1=NC2=C(N1C3C(C(C(O3)COP(=O)(CP(=O)(O)OP(=O)(O)O)O)O)O)N=C(NC2=O)N
InChI 1S/C11H18N5O13P3/c12-11-14-8-5(9(19)15-11)13-2-16(8)10-7(18)6(17)4(28-10)1-27-30(20,21)3-31(22,23)29-32(24,25)26/h2,4,6-7,10,17-18H,1,3H2,(H,20,21)(H,22,23)(H2,24,25,26)(H3,12,14,15,19)/t4-,6-,7-,10-/m1/s1
InChIKey GXTIEXDFEKYVGY-KQYNXXCUSA-N
PubChem Compound ID 135440070
Drug Binding Sites of Target  Top
PDB ID: 7ROV      KRAS G12D Mutant in complex with GMPPCP and cyclic peptide MP-9903
Method X-ray diffraction Resolution 1.32 Å Mutation Yes [1]
PDB Sequence
AMTEYKLVVV
9
GADGVGKSAL
19
TIQLIQNHFV
29
DEYDPTIEDS
39
YRKQVVIDGE
49

TCLLDILDTA
59
GQEEYSAMRD
69
QYMRTGEGFL
79
CVFAINNTKS
89
FEDIHHYREQ
99

IKRVKDSEDV
109
PMVLVGNKCD
119
LPSRTVDTKQ
129
AQDLARSYGI
139
PFIETSAKTR
149

QGVDDAFYTL
159
VREIRKHK
Residue
Distance (Å)
ALA11
4.013
ASP12
2.878
GLY13
3.501
VAL14
3.362
GLY15
3.153
LYS16
2.736
SER17
2.898
ALA18
2.739
PHE28
3.331
VAL29
4.002
THR35
4.815
ASP57
4.594
Residue
Distance (Å)
THR58
4.328
ALA59
3.905
GLN61
4.430
ASN116
3.230
LYS117
3.211
ASP119
2.750
LEU120
3.585
THR144
4.780
SER145
3.499
ALA146
2.850
LYS147
3.232
PDB ID: 4DSN      Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
Method X-ray diffraction Resolution 2.03 Å Mutation Yes [2]
PDB Sequence
STEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEKM
170
SKDGKKKKKK
180
Residue
Distance (Å)
ALA11
3.964
ASP12
3.578
GLY13
3.433
VAL14
3.247
GLY15
3.084
LYS16
2.555
SER17
2.822
ALA18
2.769
LEU19
4.984
PHE28
3.304
VAL29
2.988
ASP30
3.159
GLU31
3.319
TYR32
3.674
ASP33
4.377
Residue
Distance (Å)
PRO34
3.143
THR35
3.081
ASP57
4.789
THR58
3.977
ALA59
4.190
GLY60
3.101
ASN116
3.228
LYS117
3.239
CYS118
4.847
ASP119
2.638
LEU120
3.579
THR144
4.749
SER145
3.453
ALA146
2.752
LYS147
3.330
PDB ID: 4DST      Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
Method X-ray diffraction Resolution 2.30 Å Mutation Yes [2]
PDB Sequence
STEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEKM
170
SKDGKKKKKK
180
Residue
Distance (Å)
ALA11
3.718
ASP12
3.477
GLY13
3.336
VAL14
3.265
GLY15
3.126
LYS16
2.731
SER17
2.888
ALA18
2.747
LEU19
4.949
PHE28
3.407
VAL29
2.812
ASP30
3.029
GLU31
3.558
TYR32
3.574
ASP33
4.350
Residue
Distance (Å)
PRO34
3.236
THR35
3.141
ASP57
4.950
THR58
3.994
ALA59
4.273
GLY60
3.187
ASN116
3.269
LYS117
3.313
CYS118
4.894
ASP119
2.665
LEU120
3.398
THR144
4.625
SER145
3.438
ALA146
2.850
LYS147
3.726
PDB ID: 7T47      KRAS G12D (GppCp) with MRTX-1133
Method X-ray diffraction Resolution 1.27 Å Mutation Yes [3]
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
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ALA11
3.959
ASP12
2.730
GLY13
3.305
VAL14
3.339
GLY15
3.059
LYS16
2.802
SER17
2.925
ALA18
2.821
PHE28
3.216
VAL29
3.342
ASP30
3.104
GLU31
4.435
TYR32
3.471
ASP33
4.733
Residue
Distance (Å)
PRO34
2.562
THR35
4.603
ASP57
4.691
THR58
4.090
ALA59
3.757
ASN116
3.150
LYS117
3.143
SER118
4.829
ASP119
2.853
LEU120
3.490
THR144
4.751
SER145
3.528
ALA146
2.887
LYS147
3.565
PDB ID: 6QUU      Crystal Structure of KRAS-G12D in complex with GMP-PCP
Method X-ray diffraction Resolution 1.48 Å Mutation Yes [4]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.805
ALA11
3.161
ASP12
1.972
GLY13
1.906
VAL14
2.090
GLY15
1.969
LYS16
1.818
SER17
1.958
ALA18
1.791
LEU19
4.431
PHE28
2.692
VAL29
1.828
ASP30
2.118
GLU31
2.641
TYR32
2.642
ASP33
3.719
Residue
Distance (Å)
PRO34
2.301
THR35
2.004
ASP57
4.717
THR58
4.135
ALA59
3.787
GLY60
1.936
GLN61
2.940
ASN116
2.311
LYS117
2.394
CYS118
4.557
ASP119
1.826
LEU120
2.368
THR144
4.648
SER145
2.716
ALA146
2.018
LYS147
2.549
PDB ID: 6QUW      Crystal Structure of KRAS-G12D in Complex with Natural Product-Like Compound 9b
Method X-ray diffraction Resolution 1.24 Å Mutation Yes [4]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.811
ALA11
2.924
ASP12
2.549
GLY13
2.588
VAL14
2.693
GLY15
2.926
LYS16
2.667
SER17
2.980
ALA18
2.771
PHE28
2.821
VAL29
2.011
ASP30
2.898
GLU31
2.642
TYR32
2.989
ASP33
3.854
PRO34
3.324
Residue
Distance (Å)
THR35
2.928
ASP57
4.720
THR58
4.161
ALA59
3.997
GLY60
2.681
GLN61
3.302
ASN116
3.172
LYS117
3.148
CYS118
4.710
ASP119
1.799
LEU120
3.027
THR144
4.594
SER145
3.531
ALA146
2.813
LYS147
3.543
PDB ID: 6QUV      Crystal Structure of KRAS-G12D in complex with GMP-PCP and compound 15R
Method X-ray diffraction Resolution 1.48 Å Mutation Yes [4]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.815
ALA11
3.790
ASP12
2.623
GLY13
3.428
VAL14
3.324
GLY15
3.057
LYS16
2.724
SER17
2.968
ALA18
2.733
PHE28
3.317
VAL29
2.722
ASP30
2.933
GLU31
3.639
TYR32
3.711
ASP33
4.277
PRO34
3.299
Residue
Distance (Å)
THR35
2.903
ASP57
4.767
THR58
4.154
ALA59
4.126
GLY60
2.947
GLN61
4.191
ASN116
3.172
LYS117
3.161
CYS118
4.929
ASP119
2.786
LEU120
3.424
THR144
4.592
SER145
3.545
ALA146
2.838
LYS147
3.800
PDB ID: 6GJ5      CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 15
Method X-ray diffraction Resolution 1.50 Å Mutation Yes [5]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QAMRDQYMRT
74
GEGFLCVFAI
84
NNTKSFEDIH
94
HYREQIKRVK
104

DSEDVPMVLV
114
GNKSDLPSRT
124
VDTKQAQDLA
134
RSYGIPFIET
144
SAKTRQGVDD
154

AFYTLVREIR
164
KHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.789
ALA11
3.578
ASP12
2.777
GLY13
3.306
VAL14
3.222
GLY15
3.149
LYS16
2.742
SER17
3.045
ALA18
2.751
PHE28
3.301
VAL29
2.707
ASP30
2.911
GLU31
3.296
TYR32
3.718
ASP33
4.363
PRO34
3.486
Residue
Distance (Å)
THR35
2.841
ASP57
4.781
THR58
4.140
ALA59
3.932
GLY60
2.786
GLN61
4.137
ASN116
3.075
LYS117
3.320
SER118
4.773
ASP119
2.756
LEU120
3.354
THR144
4.650
SER145
3.460
ALA146
2.759
LYS147
3.579
PDB ID: 7ACA      CRYSTAL STRUCTURE OF AN ACTIVE KRAS G12D (GPPCP) DIMER IN COMPLEX WITH BI-5747
Method X-ray diffraction Resolution 1.57 Å Mutation Yes [6]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.877
ALA11
4.000
ASP12
3.626
GLY13
3.443
VAL14
3.283
GLY15
3.087
LYS16
2.740
SER17
2.883
ALA18
2.728
LEU19
4.957
PHE28
3.335
VAL29
2.729
ASP30
2.887
GLU31
3.540
TYR32
3.660
ASP33
4.283
Residue
Distance (Å)
PRO34
3.184
THR35
2.939
ASP57
4.656
THR58
3.974
ALA59
4.106
GLY60
3.025
GLN61
4.986
ASN116
3.099
LYS117
3.250
CYS118
4.775
ASP119
2.724
LEU120
3.533
THR144
4.532
SER145
3.418
ALA146
2.790
LYS147
3.721
PDB ID: 6QUX      Crystal Structure of KRAS-G12D in Complex with Natural Product-Like Compound 15
Method X-ray diffraction Resolution 1.62 Å Mutation Yes [4]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.801
ALA11
3.238
ASP12
1.993
GLY13
1.875
VAL14
2.070
GLY15
1.986
LYS16
1.817
SER17
1.996
ALA18
1.832
LEU19
4.397
PHE28
2.728
VAL29
1.855
ASP30
1.974
GLU31
2.502
TYR32
2.620
ASP33
3.696
Residue
Distance (Å)
PRO34
2.456
THR35
2.090
ASP57
4.752
THR58
4.172
ALA59
3.825
GLY60
1.934
GLN61
2.955
ASN116
2.315
LYS117
2.311
CYS118
4.570
ASP119
1.753
LEU120
2.175
THR144
4.640
SER145
2.677
ALA146
1.984
LYS147
2.654
PDB ID: 6GJ7      CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 22
Method X-ray diffraction Resolution 1.67 Å Mutation Yes [5]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKH
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.961
ALA11
3.762
ASP12
2.624
GLY13
3.337
VAL14
3.453
GLY15
3.269
LYS16
2.714
SER17
2.943
ALA18
2.849
PHE28
3.128
VAL29
2.870
ASP30
2.956
GLU31
3.494
TYR32
3.534
ASP33
4.245
Residue
Distance (Å)
PRO34
3.435
THR35
2.723
ASP57
4.766
THR58
4.188
ALA59
4.057
GLY60
2.916
GLN61
4.382
ASN116
3.213
LYS117
3.140
ASP119
2.774
LEU120
3.637
THR144
4.701
SER145
3.509
ALA146
2.820
LYS147
3.808
PDB ID: 6ZLI      CRYSTAL STRUCTURE OF KRAS-G12D IN COMPLEX WITH COMPOUND 13 AND GCP
Method X-ray diffraction Resolution 1.73 Å Mutation Yes [7]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.827
ALA11
3.886
ASP12
2.524
GLY13
3.397
VAL14
3.316
GLY15
3.080
LYS16
2.656
SER17
3.011
ALA18
2.791
PHE28
3.362
VAL29
2.637
ASP30
2.861
GLU31
3.509
TYR32
3.639
ASP33
4.222
PRO34
3.253
Residue
Distance (Å)
THR35
2.915
ASP57
4.788
THR58
4.074
ALA59
4.124
GLY60
2.971
GLN61
4.229
ASN116
3.143
LYS117
3.094
CYS118
4.956
ASP119
2.812
LEU120
3.502
THR144
4.704
SER145
3.543
ALA146
2.841
LYS147
3.897
PDB ID: 6GJ6      CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH 18
Method X-ray diffraction Resolution 1.76 Å Mutation Yes [5]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
SAMRDQYMRT
74
GEGFLCVFAI
84
NNTKSFEDIH
94
HYREQIKRVK
104

DSEDVPMVLV
114
GNKCDLPSRT
124
VDTKQAQDLA
134
RSYGIPFIET
144
SAKTRQGVDD
154

AFYTLVREIR
164
KHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ALA11
3.713
ASP12
2.687
GLY13
3.239
VAL14
3.353
GLY15
3.237
LYS16
2.723
SER17
3.037
ALA18
2.755
LEU19
4.988
PHE28
3.343
VAL29
2.719
ASP30
2.724
GLU31
3.487
TYR32
3.575
ASP33
4.277
Residue
Distance (Å)
PRO34
3.359
THR35
2.892
ASP57
4.664
THR58
3.995
ALA59
4.187
GLY60
3.098
ASN116
3.140
LYS117
3.280
CYS118
4.833
ASP119
2.771
LEU120
3.520
THR144
4.651
SER145
3.503
ALA146
2.772
LYS147
3.505
PDB ID: 7ACH      CRYSTAL STRUCTURE OF ACTIVE KRAS G12D (GPPCP) IN COMPLEX WITH THE SOAKED DIMERIC INHIBITOR BI-5747
Method X-ray diffraction Resolution 1.90 Å Mutation Yes [8]
PDB Sequence
MTEYKLVVVG
10
ADGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.880
ALA11
3.757
ASP12
2.666
GLY13
3.407
VAL14
3.332
GLY15
3.136
LYS16
2.753
SER17
2.990
ALA18
2.811
PHE28
3.345
VAL29
2.738
ASP30
2.879
GLU31
3.814
TYR32
3.654
ASP33
4.201
PRO34
3.283
Residue
Distance (Å)
THR35
2.854
ASP57
4.750
THR58
4.113
ALA59
4.029
GLY60
2.872
GLN61
4.184
ASN116
3.144
LYS117
3.008
CYS118
4.990
ASP119
2.737
LEU120
3.491
THR144
4.636
SER145
3.523
ALA146
2.809
LYS147
3.837
PDB ID: 7ACF      CRYSTAL STRUCTURE OF CRYSTAL FORM 2 OF AN ACTIVE KRAS G12D (GPPCP) DIMER IN COMPLEX WITH BI-5747
Method X-ray diffraction Resolution 1.91 Å Mutation Yes [9]
PDB Sequence
GMTEYKLVVV
9
GADGVGKSAL
19
TIQLIQNHFV
29
DEYDPTIEDS
39
YRKQVVIDGE
49

TCLLDILDTA
59
GQEEYSAMRD
69
QYMRTGEGFL
79
CVFAINNTKS
89
FEDIHHYREQ
99

IKRVKDSEDV
109
PMVLVGNKCD
119
LPSRTVDTKQ
129
AQDLARSYGI
139
PFIETSAKTR
149

QGVDDAFYTL
159
VREIRKHKE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.883
ALA11
3.911
ASP12
3.954
GLY13
3.425
VAL14
3.314
GLY15
3.185
LYS16
2.747
SER17
2.924
ALA18
2.801
PHE28
3.215
VAL29
2.716
ASP30
2.864
GLU31
3.439
TYR32
3.649
ASP33
4.312
PRO34
3.332
Residue
Distance (Å)
THR35
2.803
ASP57
4.539
THR58
3.949
ALA59
3.978
GLY60
2.842
GLN61
4.296
ASN116
3.136
LYS117
3.265
CYS118
4.913
ASP119
2.765
LEU120
3.529
THR144
4.616
SER145
3.407
ALA146
2.763
LYS147
3.675
PDB ID: 7LZ5      Crystal structure of oncogenic KRAS Q61E GMPPCP-bound
Method X-ray diffraction Resolution 1.50 Å Mutation Yes [10]
PDB Sequence
MTEYKLVVVG
10
AGGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
EEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKSDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.642
ALA11
3.786
GLY12
3.508
GLY13
3.292
VAL14
3.388
GLY15
3.116
LYS16
2.565
SER17
2.950
ALA18
2.772
PHE28
3.397
VAL29
2.783
ASP30
3.120
GLU31
4.004
TYR32
3.613
Residue
Distance (Å)
ASP57
4.554
THR58
4.032
ALA59
3.854
GLY60
2.777
GLU61
4.684
ASN116
3.199
LYS117
3.210
SER118
4.798
ASP119
2.797
LEU120
3.466
THR144
4.777
SER145
3.618
ALA146
2.823
LYS147
3.523
PDB ID: 6GJ8      CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH BI 2852
Method X-ray diffraction Resolution 1.65 Å Mutation Yes [5]
PDB Sequence
GMTEYKLVVV
9
GADGVGKSAL
19
TIQLIQNHFV
29
DEYDPTIEDS
39
YRKQVVIDGE
49

TCLLDILDTA
59
GQEEYSAMRD
69
QYMRTGEGFL
79
CVFAINNTKS
89
FEDIHHYREQ
99

IKRVKDSEDV
109
PMVLVGNKCD
119
LPSRTVDTKQ
129
AQDLARSYGI
139
PFIETSAKTR
149

QGVDDAFYTL
159
VREIRKHKE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:10 or .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:28 or .A:29 or .A:30 or .A:31 or .A:32 or .A:33 or .A:34 or .A:35 or .A:57 or .A:58 or .A:59 or .A:60 or .A:61 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
GLY10
4.875
ALA11
3.636
ASP12
2.626
GLY13
3.245
VAL14
3.340
GLY15
3.247
LYS16
2.746
SER17
2.929
ALA18
2.761
LEU19
4.942
PHE28
3.164
VAL29
2.693
ASP30
2.782
GLU31
3.542
TYR32
3.588
ASP33
4.352
Residue
Distance (Å)
PRO34
3.393
THR35
2.908
ASP57
4.669
THR58
4.150
ALA59
4.113
GLY60
2.922
GLN61
4.239
ASN116
3.185
LYS117
3.220
CYS118
4.848
ASP119
2.730
LEU120
3.629
THR144
4.577
SER145
3.417
ALA146
2.797
LYS147
3.714
PDB ID: 6BP1      Crystal structure of human KRAS A59G mutant in complex with GCP
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [11]
PDB Sequence
MTEYKLVVVG
10
AGGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTGG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKCDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GCP or .GCP2 or .GCP3 or :3GCP;style chemicals stick;color identity;select .A:11 or .A:12 or .A:13 or .A:14 or .A:15 or .A:16 or .A:17 or .A:18 or .A:19 or .A:34 or .A:35 or .A:37 or .A:57 or .A:58 or .A:59 or .A:60 or .A:63 or .A:116 or .A:117 or .A:118 or .A:119 or .A:120 or .A:144 or .A:145 or .A:146 or .A:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ALA11
3.009
GLY12
2.989
GLY13
1.684
VAL14
1.979
GLY15
2.049
LYS16
1.869
SER17
1.725
ALA18
2.165
LEU19
4.827
PRO34
3.003
THR35
3.318
GLU37
4.214
ASP57
3.029
Residue
Distance (Å)
THR58
2.774
GLY59
3.232
GLY60
3.920
GLU63
4.241
ASN116
2.505
LYS117
2.526
CYS118
4.729
ASP119
1.905
LEU120
2.484
THR144
4.731
SER145
2.687
ALA146
2.118
LYS147
2.707
References  Top
REF 1 Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling. Chem Sci. 2021 Nov 25;12(48):15975-15987.
REF 2 Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5299-304.
REF 3 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 4 KRAS Binders Hidden in Nature. Chemistry. 2019 Sep 18;25(52):12037-12041.
REF 5 Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15823-15829.
REF 6 CRYSTAL STRUCTURE OF AN ACTIVE KRAS G12D (GPPCP) DIMER IN COMPLEX WITH BI-5747
REF 7 Drugging all RAS isoforms with one pocket. Future Med Chem. 2020 Nov;12(21):1911-1923.
REF 8 CRYSTAL STRUCTURE OF ACTIVE KRAS G12D (GPPCP) IN COMPLEX WITH THE SOAKED DIMERIC INHIBITOR BI-5747
REF 9 Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers.. doi:10.1073/pnas.1921236117.
REF 10 Crystal structure of oncogenic KRAS Q61E GMPPCP-bound
REF 11 KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation. Biochemistry. 2018 Jan 23;57(3):324-333.

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