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 5'-Guanosine-Diphosphate-Monothiophosphate Ligand Info
Canonical SMILES C1=NC2=C(N1C3C(C(C(O3)COP(=O)(O)OP(=O)(O)OP(=S)(O)O)O)O)N=C(NC2=O)N
InChI 1S/C10H16N5O13P3S/c11-10-13-7-4(8(18)14-10)12-2-15(7)9-6(17)5(16)3(26-9)1-25-29(19,20)27-30(21,22)28-31(23,24)32/h2-3,5-6,9,16-17H,1H2,(H,19,20)(H,21,22)(H2,23,24,32)(H3,11,13,14,18)/t3-,5-,6-,9-/m1/s1
InChIKey XOFLBQFBSOEHOG-UUOKFMHZSA-N
PubChem Compound ID 135398675
Drug Binding Sites of Target  Top
PDB ID: 4DSO      Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
Method X-ray diffraction Resolution 1.85 Å Mutation Yes [1]
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)
GLY10
4.858
ALA11
3.831
ASP12
3.622
GLY13
2.873
VAL14
3.297
GLY15
2.953
LYS16
2.639
SER17
2.883
ALA18
2.837
PHE28
3.282
VAL29
2.631
ASP30
2.972
GLU31
3.444
TYR32
2.508
ASP33
4.301
PRO34
3.882
Residue
Distance (Å)
THR35
2.842
ASP57
4.600
THR58
3.896
ALA59
3.759
GLY60
2.703
GLN61
4.034
ASN116
3.211
LYS117
2.996
CYS118
4.981
ASP119
2.666
LEU120
3.257
THR144
4.834
SER145
3.495
ALA146
2.866
LYS147
3.382
PDB ID: 7SCX      KRAS full-length G12V in complex with RGL1 Ras association domain
Method X-ray diffraction Resolution 1.96 Å Mutation Yes [2]
PDB Sequence
MTEYKLVVVG
10
AVGVGKSALT
20
IQLIQNHFVD
30
EYDPTIEDSY
40
RKQVVIDGET
50

CLLDILDTAG
60
QEEYSAMRDQ
70
YMRTGEGFLC
80
VFAINNTKSF
90
EDIHHYREQI
100

KRVKDSEDVP
110
MVLVGNKSDL
120
PSRTVDTKQA
130
QDLARSYGIP
140
FIETSAKTRQ
150

GVDDAFYTLV
160
REIRKHKEK
Residue
Distance (Å)
GLY10
4.545
ALA11
3.899
VAL12
2.895
GLY13
2.160
VAL14
2.930
GLY15
2.176
LYS16
1.674
SER17
2.889
ALA18
2.049
LEU19
4.625
PHE28
2.371
VAL29
3.594
ASP30
2.274
GLU31
2.864
TYR32
3.982
ASP33
3.974
PRO34
2.963
Residue
Distance (Å)
THR35
1.909
ASP57
4.650
THR58
3.297
ALA59
3.417
GLY60
1.970
GLN61
3.567
ASN116
2.425
LYS117
2.610
SER118
4.520
ASP119
2.016
LEU120
2.618
THR144
4.734
SER145
2.692
ALA146
2.239
LYS147
2.717
THR148
4.987
PDB ID: 7SCW      KRAS full length wild-type in complex with RGL1 Ras association domain
Method X-ray diffraction Resolution 1.98 Å Mutation Yes [2]
PDB Sequence
GSMTEYKLVV
8
VGAGGVGKSA
18
LTIQLIQNHF
28
VDEYDPTIED
38
SYRKQVVIDG
48

ETCLLDILDT
58
AGQEEYSAMR
68
DQYMRTGEGF
78
LCVFAINNTK
88
SFEDIHHYRE
98

QIKRVKDSED
108
VPMVLVGNKS
118
DLPSRTVDTK
128
QAQDLARSYG
138
IPFIETSAKT
148

RQGVDDAFYT
158
LVREIRKHKE
168
K
Residue
Distance (Å)
GLY10
4.644
ALA11
3.893
GLY12
2.607
GLY13
2.022
VAL14
2.877
GLY15
2.264
LYS16
1.778
SER17
2.204
ALA18
2.071
LEU19
4.630
PHE28
2.544
VAL29
3.710
ASP30
2.456
GLU31
2.688
TYR32
3.825
ASP33
4.019
Residue
Distance (Å)
PRO34
2.951
THR35
2.136
ASP57
4.642
THR58
2.970
ALA59
3.184
GLY60
1.966
GLN61
3.686
ASN116
2.472
LYS117
2.539
SER118
4.432
ASP119
1.905
LEU120
2.557
THR144
4.554
SER145
2.672
ALA146
2.150
LYS147
3.223
PDB ID: 6W4E      NMR-driven structure of KRAS4B-GTP homodimer on a lipid bilayer nanodisc
Method Solution NMR Resolution N.A. Mutation No [3]
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
SKTK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;style chemicals stick;color identity;select .B:11 or .B:12 or .B:13 or .B:14 or .B:15 or .B:16 or .B:17 or .B:18 or .B:19 or .B:28 or .B:29 or .B:30 or .B:31 or .B:32 or .B:33 or .B:34 or .B:35 or .B:57 or .B:60 or .B:116 or .B:117 or .B:118 or .B:119 or .B:120 or .B:145 or .B:146 or .B:147; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ALA11
3.978
ASP12
3.717
GLY13
2.056
VAL14
2.221
GLY15
2.065
LYS16
2.312
SER17
1.635
ALA18
1.840
LEU19
4.362
PHE28
2.778
VAL29
3.596
ASP30
2.463
GLU31
4.289
TYR32
2.663
Residue
Distance (Å)
ASP33
2.756
PRO34
3.160
THR35
1.689
ASP57
2.602
GLY60
4.873
ASN116
2.130
LYS117
2.011
CYS118
4.483
ASP119
2.921
LEU120
3.007
SER145
4.095
ALA146
2.179
LYS147
1.995
PDB ID: 7RSE      NMR-driven structure of the KRAS4B-G12D "alpha-beta" dimer on a lipid bilayer nanodisc
Method Solution NMR Resolution N.A. Mutation Yes [4]
PDB Sequence
TEYKLVVVGA
11
DGVGKSALTI
21
QLIQNHFVDE
31
YDPTIEDSYR
41
KQVVIDGETC
51

LLDILDTAGQ
61
EEYSAMRDQY
71
MRTGEGFLCV
81
FAINNTKSFE
91
DIHHYREQIK
101

RVKDSEDVPM
111
VLVGNKCDLP
121
SRTVDTKQAQ
131
DLARSYGIPF
141
IETSAKTRQG
151

VDDAFYTLVR
161
EIRKHKEKMS
171
KDGKKKKKKS
181
KTK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;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: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:145 or .A:146 or .A:147 or .A:148; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ALA11
4.201
ASP12
4.289
GLY13
3.205
VAL14
2.858
GLY15
1.737
LYS16
1.769
SER17
1.688
ALA18
2.039
LEU19
4.648
ASP30
4.637
GLU31
3.944
TYR32
3.128
ASP33
1.963
PRO34
3.521
Residue
Distance (Å)
THR35
2.395
ASP57
2.505
THR58
2.753
ALA59
3.439
GLY60
1.982
GLN61
4.393
ASN116
1.848
LYS117
2.862
ASP119
2.206
LEU120
2.971
SER145
2.526
ALA146
1.937
LYS147
1.669
THR148
3.984
PDB ID: 5VPZ      Crystal structure of human KRAS G12A mutant in complex with GTP-gamma-S
Method X-ray diffraction Resolution 1.85 Å Mutation Yes [5]
PDB Sequence
HMTEYKLVVV
9
GAAGVGKSAL
19
TIQLIQNHFV
29
DEYDPDSYRK
42
QVVIDGETCL
52

LDILDTADQY
71
MRTGEGFLCV
81
FAINNTKSFE
91
DIHHYREQIK
101
RVKDSEDVPM
111

VLVGNKSDLP
121
SRTVDTKQAQ
131
DLARSYGIPF
141
IETSAKTRQG
151
VDDAFYTLVR
161

EIRKHKEK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;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:34 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)
GLY10
4.905
ALA11
3.828
ALA12
3.783
GLY13
3.120
VAL14
3.387
GLY15
3.170
LYS16
2.746
SER17
2.986
ALA18
2.868
PHE28
3.367
VAL29
3.110
ASP30
2.772
GLU31
4.627
TYR32
4.764
Residue
Distance (Å)
PRO34
3.582
ASP57
4.535
THR58
4.114
ALA59
3.113
ASN116
3.193
LYS117
3.328
SER118
4.751
ASP119
2.840
LEU120
3.527
THR144
4.730
SER145
3.472
ALA146
2.903
LYS147
3.507
PDB ID: 5VQ6      Crystal structure of human WT-KRAS in complex with GTP-gamma-S
Method X-ray diffraction Resolution 1.99 Å Mutation Yes [5]
PDB Sequence
HMTEYKLVVV
9
GAGGVGKSAL
19
TIQLIQNHFV
29
DEYDSYRKQV
44
VIDGETCLLD
54

ILDTADQYMR
73
TGEGFLCVFA
83
INNTKSFEDI
93
HHYREQIKRV
103
KDSEDVPMVL
113

VGNKSDLPSR
123
TVDTKQAQDL
133
ARSYGIPFIE
143
TSAKTRQGVD
153
DAFYTLVREI
163

RKHKE
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;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: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
4.669
ALA11
3.778
GLY12
3.499
GLY13
3.078
VAL14
3.197
GLY15
3.052
LYS16
2.742
SER17
2.969
ALA18
2.857
PHE28
3.354
VAL29
3.339
ASP30
3.022
GLU31
4.814
Residue
Distance (Å)
TYR32
4.876
ASP57
4.351
THR58
4.160
ALA59
3.146
ASN116
3.157
LYS117
3.223
SER118
4.817
ASP119
2.747
LEU120
3.601
THR144
4.697
SER145
3.511
ALA146
2.816
LYS147
3.453
PDB ID: 5MLA      Crystal structure of human RAS in complex with darpin K55
Method X-ray diffraction Resolution 2.19 Å Mutation Yes [6]
PDB Sequence
MTEYKLVVVG
10
AVGVGKSALT
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
REIR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;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
4.803
ALA11
3.823
VAL12
3.973
GLY13
2.932
VAL14
3.138
GLY15
3.013
LYS16
2.582
SER17
2.976
ALA18
2.779
PHE28
3.284
VAL29
2.799
ASP30
2.762
GLU31
4.422
TYR32
4.234
ASP33
4.019
PRO34
3.922
Residue
Distance (Å)
THR35
2.650
ASP57
4.662
THR58
3.653
ALA59
3.821
GLY60
2.748
GLN61
4.322
ASN116
3.151
LYS117
3.217
CYS118
4.863
ASP119
2.679
LEU120
3.603
THR144
4.723
SER145
3.532
ALA146
2.974
LYS147
3.503
PDB ID: 5O2T      Human KRAS in complex with darpin K27
Method X-ray diffraction Resolution 2.19 Å Mutation Yes [7]
PDB Sequence
MTEYKLVVVG
10
AVGVGKSALT
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
REIR
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GSP or .GSP2 or .GSP3 or :3GSP;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
4.803
ALA11
3.823
VAL12
3.973
GLY13
2.932
VAL14
3.138
GLY15
3.013
LYS16
2.582
SER17
2.976
ALA18
2.779
PHE28
3.284
VAL29
2.799
ASP30
2.762
GLU31
4.422
TYR32
4.234
ASP33
4.019
PRO34
3.922
Residue
Distance (Å)
THR35
2.650
ASP57
4.662
THR58
3.653
ALA59
3.821
GLY60
2.748
GLN61
4.322
ASN116
3.151
LYS117
3.217
CYS118
4.863
ASP119
2.679
LEU120
3.603
THR144
4.723
SER145
3.532
ALA146
2.974
LYS147
3.503
References  Top
REF 1 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 2 Structures of RGL1 RAS-Association Domain in Complex with KRAS and the Oncogenic G12V Mutant. J Mol Biol. 2022 May 15;434(9):167527.
REF 3 Two Distinct Structures of Membrane-Associated Homodimers of GTP- and GDP-Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement. Angew Chem Int Ed Engl. 2020 Jun 26;59(27):11037-11045.
REF 4 Oncogenic KRAS G12D mutation promotes dimerization through a second, phosphatidylserine-dependent interface: a model for KRAS oligomerization. Chem Sci. 2021 Sep 7;12(38):12827-12837.
REF 5 Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras. Acta Crystallogr D Struct Biol. 2017 Dec 1;73(Pt 12):970-984.
REF 6 Crystal structure of human RAS in complex with darpin K55
REF 7 Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange. Nat Commun. 2017 Jul 14;8:16111.

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