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- PDB-8aq7: KRAS G12C IN COMPLEX WITH GDP AND COMPOUND 9 -

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Basic information

Entry
Database: PDB / ID: 8aq7
TitleKRAS G12C IN COMPLEX WITH GDP AND COMPOUND 9
ComponentsGTPase KRas
KeywordsHYDROLASE / K-RAS G12C / GTPASE / GDP BOUND / CYSTEINE MUTATION / COVALENT BINDING / SIGNALING PROTEIN / SMALL G-PROTEIN / SWITCH2 POCKET
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 / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / 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 / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Negative regulation of MAPK 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 / Signaling by CSF1 (M-CSF) in myeloid cells / GDP binding / 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 / Chem-NZX / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsOstermann, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS G12C for the Treatment of Solid Tumors.
Authors: Lorthiois, E. / Gerspacher, M. / Beyer, K.S. / Vaupel, A. / Leblanc, C. / Stringer, R. / Weiss, A. / Wilcken, R. / Guthy, D.A. / Lingel, A. / Bomio-Confaglia, C. / Machauer, R. / Rigollier, ...Authors: Lorthiois, E. / Gerspacher, M. / Beyer, K.S. / Vaupel, A. / Leblanc, C. / Stringer, R. / Weiss, A. / Wilcken, R. / Guthy, D.A. / Lingel, A. / Bomio-Confaglia, C. / Machauer, R. / Rigollier, P. / Ottl, J. / Arz, D. / Bernet, P. / Desjonqueres, G. / Dussauge, S. / Kazic-Legueux, M. / Lozac'h, M.A. / Mura, C. / Sorge, M. / Todorov, M. / Warin, N. / Zink, F. / Voshol, H. / Zecri, F.J. / Sedrani, R.C. / Ostermann, N. / Brachmann, S.M. / Cotesta, S.
History
DepositionAug 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 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
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5569
Polymers38,7062
Non-polymers1,8517
Water5,693316
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2905
Polymers19,3531
Non-polymers9374
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2664
Polymers19,3531
Non-polymers9133
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.408, 64.791, 132.621
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: 19352.785 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P01116
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-NZX / 1-[6-[3-cyclohexyl-5-methyl-4-(5-methyl-1~{H}-indazol-4-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]propan-1-one / 1-[6-[3-cyclohexyl-5-methyl-4-(5-methyl-1H-indazol-4-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one (precursor)


Mass: 445.600 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H35N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 316 / 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: 2.41 Å3/Da / Density % sol: 48.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 30 % PEG 4000, 0.1 M Tris pH 8.5, 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 1.65→66.31 Å / Num. obs: 45907 / % possible obs: 99.9 % / Redundancy: 6.49 % / Rmerge(I) obs: 0.039 / Net I/σ(I): 24.48
Reflection shellResolution: 1.65→1.69 Å / Redundancy: 6.65 % / Rmerge(I) obs: 0.621 / Mean I/σ(I) obs: 2.85 / Num. unique obs: 3360 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (3-FEB-2022)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7R0M

7r0m


Resolution: 1.65→32.4 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.108 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.116 / SU Rfree Blow DPI: 0.115 / SU Rfree Cruickshank DPI: 0.11
RfactorNum. reflection% reflectionSelection details
Rfree0.253 2143 -RANDOM
Rwork0.2115 ---
obs0.2135 44949 97.9 %-
Displacement parametersBiso mean: 30.71 Å2
Baniso -1Baniso -2Baniso -3
1-2.5279 Å20 Å20 Å2
2---0.3076 Å20 Å2
3----2.2203 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.65→32.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2604 0 125 316 3045
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082853HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.943886HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1021SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes486HARMONIC5
X-RAY DIFFRACTIONt_it2853HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2793SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion16.39
LS refinement shellResolution: 1.65→1.66 Å
RfactorNum. reflection% reflection
Rfree0.2412 53 -
Rwork0.2386 --
obs0.2388 899 78.61 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.2345-1.12990.80613.2698-1.62212.2928-0.20770.3728-0.34730.3728-0.0276-0.1047-0.3473-0.10470.23530.030.0056-0.0479-0.05080.0039-0.0248-18.87964.5055-11.2338
20.69170.03440.39091.22550.29033.070.05-0.05730.3706-0.0573-0.0180.14390.37060.1439-0.03190.05090.0255-0.0057-0.0174-0.0126-0.0603-6.9786-26.1789-22.3545
31.0853-1.14970.86461.42470.35930.8379-0.16980.23880.06910.23880.05670.17170.06910.17170.113-0.0204-0.0389-0.01590.00110.03840.0031-5.9414-10.975-11.8313
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 168
2X-RAY DIFFRACTION1{ A|* }A1001 - 1004
3X-RAY DIFFRACTION2{ B|* }B1 - 167
4X-RAY DIFFRACTION2{ B|* }B1001 - 1003

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