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- PDB-9kpm: Crystal structure of KRAS-G12C in complex with compound 16 (JAB-16) -

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Basic information

Entry
Database: PDB / ID: 9kpm
TitleCrystal structure of KRAS-G12C in complex with compound 16 (JAB-16)
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS4B / G12C / GTPase / inhibitor
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / RAF activation / liver development / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsLi, S. / Dang, C. / Fan, X. / Zhang, W. / Wang, P. / Qian, D. / Wang, Y. / Li, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS G12C.
Authors: Li, A. / Li, S. / Wang, P. / Dang, C. / Fan, X. / Chen, M. / Liu, D. / Li, F. / Liu, H. / Zhang, W. / Wang, Y. / Wang, Y.
History
DepositionNov 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3394
Polymers21,2171
Non-polymers1,1223
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.690, 86.690, 42.680
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Components on special symmetry positions
IDModelComponents
11A-487-

HOH

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Components

#1: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 21216.910 Da / Num. of mol.: 1 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Details: MGHHHHHHENLYFQS belongs to the fusion tag and TEV cleavage site. After cleavage, an extra residue Ser was left before the starting Met residue.
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-A1L6C / 7-[2-azanyl-3,5-bis(chloranyl)-6-fluoranyl-phenyl]-6-chloranyl-1-(4-methyl-2-propan-2-yl-pyridin-3-yl)-2-oxidanylidene-4-(4-prop-2-enoylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile


Mass: 654.949 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H27Cl3FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.39 Å3/Da / Density % sol: 43.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 0.2 M Magnesium Chloride, 0.1 M Tris pH 8.3, 25% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12713 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12713 Å / Relative weight: 1
ReflectionResolution: 1.41→43.383 Å / Num. obs: 35392 / % possible obs: 99.7 % / Redundancy: 13.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Net I/σ(I): 25.1
Reflection shellResolution: 1.41→1.43 Å / Rmerge(I) obs: 0.716 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 1692 / CC1/2: 0.766

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→43.383 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.953 / SU B: 1.019 / SU ML: 0.04 / Cross valid method: THROUGHOUT / ESU R: 0.064 / ESU R Free: 0.062
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1936 1796 5.084 %
Rwork0.1792 33533 -
all0.18 --
obs-35329 99.555 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 12.698 Å2
Baniso -1Baniso -2Baniso -3
1--0.266 Å2-0.133 Å2-0 Å2
2---0.266 Å20 Å2
3---0.863 Å2
Refinement stepCycle: LAST / Resolution: 1.41→43.383 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1349 0 73 190 1612
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0131502
X-RAY DIFFRACTIONr_bond_other_d0.0010.0151373
X-RAY DIFFRACTIONr_angle_refined_deg1.4381.7332039
X-RAY DIFFRACTIONr_angle_other_deg1.371.6293164
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5485178
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.27422.23585
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.18415261
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3721512
X-RAY DIFFRACTIONr_chiral_restr0.0650.2191
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021711
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02345
X-RAY DIFFRACTIONr_nbd_refined0.210.2270
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1750.21266
X-RAY DIFFRACTIONr_nbtor_refined0.1680.2733
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.2645
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1250.2142
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0960.21
X-RAY DIFFRACTIONr_nbd_other0.140.232
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1650.216
X-RAY DIFFRACTIONr_mcbond_it0.8191.174697
X-RAY DIFFRACTIONr_mcbond_other0.8161.17696
X-RAY DIFFRACTIONr_mcangle_it1.4171.755877
X-RAY DIFFRACTIONr_mcangle_other1.4171.76878
X-RAY DIFFRACTIONr_scbond_it1.1111.346805
X-RAY DIFFRACTIONr_scbond_other1.1121.348801
X-RAY DIFFRACTIONr_scangle_it1.7761.9661161
X-RAY DIFFRACTIONr_scangle_other1.7751.9661162
X-RAY DIFFRACTIONr_lrange_it3.92414.811776
X-RAY DIFFRACTIONr_lrange_other3.76714.3411743
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.41-1.4470.3551180.3982438X-RAY DIFFRACTION96.4892
1.447-1.4860.2891160.2812388X-RAY DIFFRACTION98.5051
1.486-1.5290.2341250.2122328X-RAY DIFFRACTION99.6344
1.529-1.5760.1871070.1812288X-RAY DIFFRACTION100
1.576-1.6280.1981300.1832186X-RAY DIFFRACTION100
1.628-1.6850.2151270.1822116X-RAY DIFFRACTION99.9554
1.685-1.7490.2151020.1782067X-RAY DIFFRACTION100
1.749-1.820.211990.1772011X-RAY DIFFRACTION100
1.82-1.9010.21940.1851916X-RAY DIFFRACTION100
1.901-1.9940.211970.1821817X-RAY DIFFRACTION99.7394
1.994-2.1020.202860.1651749X-RAY DIFFRACTION99.9455
2.102-2.2290.171020.1681632X-RAY DIFFRACTION100
2.229-2.3830.139880.1591536X-RAY DIFFRACTION99.8156
2.383-2.5730.174880.1571427X-RAY DIFFRACTION100
2.573-2.8190.187610.1641347X-RAY DIFFRACTION100
2.819-3.1510.211800.1751193X-RAY DIFFRACTION100
3.151-3.6370.184640.1631067X-RAY DIFFRACTION99.9117
3.637-4.4520.184390.156920X-RAY DIFFRACTION99.8958
4.452-6.2850.158500.171697X-RAY DIFFRACTION99.8663

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