Target Binding Site Detail
Target General Information | Top | ||||
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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 |
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 | |||||
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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 ADGVGKSALT20 IQLIQNHFVD30 EYDPTIEDSY40 RKQVVIDGET50 CLLDILDTAG 60 QEEYSAMRDQ70 YMRTGEGFLC80 VFAINNTKSF90 EDIHHYREQI100 KRVKDSEDVP 110 MVLVGNKCDL120 PSRTVDTKQA130 QDLARSYGIP140 FIETSAKTRQ150 GVDDAFYTLV 160 REIRKHKEKM170 SKDGKKKKKK180
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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
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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 AVGVGKSALT20 IQLIQNHFVD30 EYDPTIEDSY40 RKQVVIDGET50 CLLDILDTAG 60 QEEYSAMRDQ70 YMRTGEGFLC80 VFAINNTKSF90 EDIHHYREQI100 KRVKDSEDVP 110 MVLVGNKSDL120 PSRTVDTKQA130 QDLARSYGIP140 FIETSAKTRQ150 GVDDAFYTLV 160 REIRKHKEK
|
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|
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
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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 VGAGGVGKSA18 LTIQLIQNHF28 VDEYDPTIED38 SYRKQVVIDG48 ETCLLDILDT 58 AGQEEYSAMR68 DQYMRTGEGF78 LCVFAINNTK88 SFEDIHHYRE98 QIKRVKDSED 108 VPMVLVGNKS118 DLPSRTVDTK128 QAQDLARSYG138 IPFIETSAKT148 RQGVDDAFYT 158 LVREIRKHKE168 K
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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
|
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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 | [3] |
PDB Sequence |
TEYKLVVVGA
11 DGVGKSALTI21 QLIQNHFVDE31 YDPTIEDSYR41 KQVVIDGETC51 LLDILDTAGQ 61 EEYSAMRDQY71 MRTGEGFLCV81 FAINNTKSFE91 DIHHYREQIK101 RVKDSEDVPM 111 VLVGNKCDLP121 SRTVDTKQAQ131 DLARSYGIPF141 IETSAKTRQG151 VDDAFYTLVR 161 EIRKHKEKMS171 KDGKKKKKKS181 KTK
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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 #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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
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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 | [4] |
PDB Sequence |
HMTEYKLVVV
9 GAAGVGKSAL19 TIQLIQNHFV29 DEYDPDSYRK42 QVVIDGETCL52 LDILDTADQY 71 MRTGEGFLCV81 FAINNTKSFE91 DIHHYREQIK101 RVKDSEDVPM111 VLVGNKSDLP 121 SRTVDTKQAQ131 DLARSYGIPF141 IETSAKTRQG151 VDDAFYTLVR161 EIRKHKEK |
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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 #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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
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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 | [4] |
PDB Sequence |
HMTEYKLVVV
9 GAGGVGKSAL19 TIQLIQNHFV29 DEYDSYRKQV44 VIDGETCLLD54 ILDTADQYMR 73 TGEGFLCVFA83 INNTKSFEDI93 HHYREQIKRV103 KDSEDVPMVL113 VGNKSDLPSR 123 TVDTKQAQDL133 ARSYGIPFIE143 TSAKTRQGVD153 DAFYTLVREI163 RKHKE |
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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 #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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
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PDB ID: 5MLA Crystal structure of human RAS in complex with darpin K55 | ||||||
Method | X-ray diffraction | Resolution | 2.19 Å | Mutation | Yes | [5] |
PDB Sequence |
MTEYKLVVVG
10 AVGVGKSALT20 IQLIQNHFVD30 EYDPTIEDSY40 RKQVVIDGET50 CLLDILDTAG 60 QEEYSAMRDQ70 YMRTGEGFLC80 VFAINNTKSF90 EDIHHYREQI100 KRVKDSEDVP 110 MVLVGNKCDL120 PSRTVDTKQA130 QDLARSYGIP140 FIETSAKTRQ150 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
|
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
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PDB ID: 5O2T Human KRAS in complex with darpin K27 | ||||||
Method | X-ray diffraction | Resolution | 2.19 Å | Mutation | Yes | [6] |
PDB Sequence |
MTEYKLVVVG
10 AVGVGKSALT20 IQLIQNHFVD30 EYDPTIEDSY40 RKQVVIDGET50 CLLDILDTAG 60 QEEYSAMRDQ70 YMRTGEGFLC80 VFAINNTKSF90 EDIHHYREQI100 KRVKDSEDVP 110 MVLVGNKCDL120 PSRTVDTKQA130 QDLARSYGIP140 FIETSAKTRQ150 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
|
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
|
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 | 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 4 | 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 5 | Crystal structure of human RAS in complex with darpin K55 | ||||
REF 6 | Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange. Nat Commun. 2017 Jul 14;8:16111. |
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