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- PDB-7a1x: KRASG12C GDP form in complex with Cpd1 -

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Basic information

Entry
Database: PDB / ID: 7a1x
TitleKRASG12C GDP form in complex with Cpd1
ComponentsGTPase KRas
KeywordsONCOPROTEIN / inhibitor / mutant
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / 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 CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family 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 / 3-(imidazol-1-ylmethyl)-1~{H}-indole / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.32 Å
AuthorsMathieu, M. / Steier, V.
CitationJournal: Small Gtpases / Year: 2022
Title: KRAS G12C fragment screening renders new binding pockets.
Authors: Mathieu, M. / Steier, V. / Fassy, F. / Delorme, C. / Papin, D. / Genet, B. / Duffieux, F. / Bertrand, T. / Delarbre, L. / Le-Borgne, H. / Parent, A. / Didier, P. / Marquette, J.P. / ...Authors: Mathieu, M. / Steier, V. / Fassy, F. / Delorme, C. / Papin, D. / Genet, B. / Duffieux, F. / Bertrand, T. / Delarbre, L. / Le-Borgne, H. / Parent, A. / Didier, P. / Marquette, J.P. / Lowinski, M. / Houtmann, J. / Lamberton, A. / Debussche, L. / Alexey, R.
History
DepositionAug 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 12, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0404
Polymers19,3751
Non-polymers6653
Water4,738263
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area8350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.07, 40.69, 91.51
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19374.902 Da / Num. of mol.: 1 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pET-28a / Details (production host): T7 promoter / Cell (production host): NA / Cell line (production host): NA / Organ (production host): NA / Production host: Escherichia coli BL21(DE3) (bacteria) / Tissue (production host): NA / Variant (production host): NA / 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 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-QWB / 3-(imidazol-1-ylmethyl)-1~{H}-indole / Cpd1


Mass: 197.236 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H11N3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.88 Å3/Da / Density % sol: 34.48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: TRIS 100mM - PEG 4K 23% - Na Acet 100mM - pH8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.32→45.76 Å / Num. obs: 35010 / % possible obs: 99.8 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 26.3
Reflection shellResolution: 1.32→1.36 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.077 / Mean I/σ(I) obs: 14.4 / Num. unique obs: 2516 / % possible all: 97.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 1.32→18.08 Å / Cor.coef. Fo:Fc: 0.9675 / Cor.coef. Fo:Fc free: 0.96 / SU R Cruickshank DPI: 0.047 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.053 / SU Rfree Blow DPI: 0.055 / SU Rfree Cruickshank DPI: 0.05
RfactorNum. reflection% reflectionSelection details
Rfree0.1739 1747 5 %RANDOM
Rwork0.148 ---
obs-34931 99.56 %-
Displacement parametersBiso mean: 13.61 Å2
Baniso -1Baniso -2Baniso -3
1-0.5893 Å20 Å20 Å2
2---1.0604 Å20 Å2
3---0.4711 Å2
Refine analyzeLuzzati coordinate error obs: 0.129 Å
Refinement stepCycle: LAST / Resolution: 1.32→18.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1357 0 44 263 1664
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011438HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.011949HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d522SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes43HARMONIC2
X-RAY DIFFRACTIONt_gen_planes219HARMONIC5
X-RAY DIFFRACTIONt_it1438HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_chiral_improper_torsion188SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1958SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.39
X-RAY DIFFRACTIONt_other_torsion14.55
LS refinement shellResolution: 1.32→1.36 Å /
RfactorNum. reflection
Rfree0.1929 135

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