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 Cysteine Sulfenic Acid Ligand Info
Canonical SMILES C(C(C(=O)O)N)SO
InChI 1S/C3H7NO3S/c4-2(1-8-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1
InChIKey FXIRVRPOOYSARH-REOHCLBHSA-N
PubChem Compound ID 165339
Drug Binding Sites of Target  Top
PDB ID: 5OCO      Discovery of small molecules binding to KRAS via high affinity antibody fragment competition method.
Method X-ray diffraction Resolution 1.66 Å Mutation Yes [1]
PDB Sequence
YFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
EK
Residue
Distance (Å)
MET1
4.324
THR2
3.121
TYR4
3.441
LYS42
3.830
GLN43
3.275
VAL44
2.796
VAL45
4.914
Residue
Distance (Å)
ILE46
4.051
GLU49
3.258
THR50
1.327
LEU52
1.321
LEU53
3.913
VAL160
4.155
ARG164
2.494
PDB ID: 5OCT      Discovery of small molecules binding to KRAS via high affinity antibody fragment competition method.
Method X-ray diffraction Resolution 2.07 Å Mutation Yes [1]
PDB Sequence
YFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
E
Residue
Distance (Å)
MET1
4.183
THR2
3.002
TYR4
3.501
LYS42
3.787
GLN43
3.216
VAL44
2.730
VAL45
4.829
Residue
Distance (Å)
ILE46
3.961
GLU49
3.228
THR50
1.328
LEU52
1.318
LEU53
3.920
VAL160
4.226
ARG164
2.545
PDB ID: 6FA1      Antibody derived (Abd-4) small molecule binding to KRAS.
Method X-ray diffraction Resolution 1.97 Å Mutation Yes [1]
PDB Sequence
> Chain A
AFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
E
> Chain B
AFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
EK
Residue [Chain]
Distance (Å)
MET1[A]
4.244
THR2[A]
3.110
TYR4[A]
3.474
LYS42[A]
3.805
GLN43[A]
3.211
VAL44[A]
2.767
VAL45[A]
4.865
ILE46[A]
4.058
GLU49[A]
3.160
THR50[A]
1.321
LEU52[A]
1.309
LEU53[A]
3.900
VAL160[A]
4.272
ARG164[A]
2.533
Residue [Chain]
Distance (Å)
MET1[B]
4.270
THR2[B]
3.114
TYR4[B]
3.438
LYS42[B]
3.787
GLN43[B]
3.212
VAL44[B]
2.764
VAL45[B]
4.909
ILE46[B]
4.046
GLU49[B]
3.191
THR50[B]
1.324
LEU52[B]
1.317
LEU53[B]
3.880
VAL160[B]
4.185
ARG164[B]
2.507
PDB ID: 6FA4      Antibody derived (Abd-7) small molecule binding to KRAS.
Method X-ray diffraction Resolution 2.02 Å Mutation Yes [1]
PDB Sequence
AFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
EK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CSO or .CSO2 or .CSO3 or :3CSO;style chemicals stick;color identity;select .B:1 or .B:2 or .B:4 or .B:42 or .B:43 or .B:44 or .B:45 or .B:46 or .B:49 or .B:50 or .B:52 or .B:53 or .B:160 or .B:164; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET1
4.297
THR2
3.233
TYR4
3.520
LYS42
3.754
GLN43
3.279
VAL44
2.759
VAL45
4.909
Residue
Distance (Å)
ILE46
4.049
GLU49
3.295
THR50
1.332
LEU52
1.325
LEU53
3.959
VAL160
4.208
ARG164
2.236
PDB ID: 6GOM      KRAS-169 Q61H GPPNHP + PPIN-1
Method X-ray diffraction Resolution 1.63 Å Mutation Yes [2]
PDB Sequence
FQGMTEYKLV
7
VVGAGGVGKS
17
ALTIQLIQNH
27
FVDEYDPTIE
37
DSYRKQVVID
47

GETLLDILDT
58
AGHEEYSAMR
68
DQYMRTGEGF
78
LCVFAINNTK
88
SFEDIHHYRE
98

QIKRVKDSED
108
VPMVLVGNKC
118
DLPSRTVDTK
128
QAQDLARSYG
138
IPFIETSAKT
148

RQGVDDAFYT
158
LVREIRKHKE
168
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CSO or .CSO2 or .CSO3 or :3CSO;style chemicals stick;color identity;select .A:1 or .A:2 or .A:4 or .A:42 or .A:43 or .A:44 or .A:45 or .A:46 or .A:49 or .A:50 or .A:52 or .A:53 or .A:160 or .A:164; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET1
4.349
THR2
3.144
TYR4
3.572
LYS42
3.904
GLN43
3.347
VAL44
2.866
VAL45
4.959
Residue
Distance (Å)
ILE46
4.151
GLU49
3.253
THR50
1.327
LEU52
1.345
LEU53
4.020
VAL160
4.463
ARG164
2.546
PDB ID: 6FA3      Antibody derived (Abd-6) small molecule binding to KRAS.
Method X-ray diffraction Resolution 1.82 Å Mutation Yes [1]
PDB Sequence
AFQGMTEYKL
6
VVVGAGGVGK
16
SALTIQLIQN
26
HFVDEYDPTI
36
EDSYRKQVVI
46

DGETLLDILD
57
TAGHEEYSAM
67
RDQYMRTGEG
77
FLCVFAINNT
87
KSFEDIHHYR
97

EQIKRVKDSE
107
DVPMVLVGNK
117
CDLPSRTVDT
127
KQAQDLARSY
137
GIPFIETSAK
147

TRQGVDDAFY
157
TLVREIRKHK
167
E
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CSO or .CSO2 or .CSO3 or :3CSO;style chemicals stick;color identity;select .B:1 or .B:2 or .B:4 or .B:42 or .B:43 or .B:44 or .B:45 or .B:46 or .B:49 or .B:50 or .B:52 or .B:53 or .B:160 or .B:164; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
MET1
4.421
THR2
3.089
TYR4
3.490
LYS42
3.785
GLN43
3.199
VAL44
2.786
VAL45
4.879
Residue
Distance (Å)
ILE46
4.059
GLU49
3.232
THR50
1.341
LEU52
1.321
LEU53
3.901
VAL160
4.208
ARG164
2.444
PDB ID: 6MQG      Crystal structure of KRAS V14I-GDP demonstrating open switch 1 conformation - Form 1
Method X-ray diffraction Resolution 1.50 Å Mutation Yes [3]
PDB Sequence
EYKLVVVGAG
12
GIGKSALTIQ
22
LIQNHFVDEY
32
DPTIEDSYRK
42
QVVIDGETCL
52

LDILDTAGQE
62
EYSAMRDQYM
72
RTGEGFLCVF
82
AINNTKSFED
92
IHHYREQIKR
102

VKDSEDVPMV
112
LVGNKDLPSR
123
TVDTKQAQDL
133
ARSYGIPFIE
143
TSAKTRQGVD
153

DAFYTLVREI
163
RKHKEK
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CSO or .CSO2 or .CSO3 or :3CSO;style chemicals stick;color identity;select .A:84 or .A:115 or .A:116 or .A:117 or .A:119 or .A:120 or .A:123 or .A:143 or .A:144 or .A:145 or .A:148 or .A:150; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ILE84
2.284
GLY115
3.540
ASN116
3.174
LYS117
1.329
ASP119
1.333
LEU120
2.835
Residue
Distance (Å)
ARG123
3.302
GLU143
2.442
THR144
2.120
SER145
2.972
THR148
3.772
GLN150
2.233
References  Top
REF 1 Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun. 2018 Aug 9;9(1):3169.
REF 2 Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2545-2550.
REF 3 Structural basis of the atypical activation mechanism of KRAS(V14I). J Biol Chem. 2019 Sep 20;294(38):13964-13972.

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