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- PDB-8aq5: KRAS G12C IN COMPLEX WITH GDP AND COMPOUND 16 -

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Basic information

Entry
Database: PDB / ID: 8aq5
TitleKRAS G12C IN COMPLEX WITH GDP AND COMPOUND 16
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 / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / 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) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 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 / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / 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 / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / 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 / Negative regulation of MAPK pathway / RAS processing / Signaling by RAF1 mutants / GDP binding / 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 / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / 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-NZ6 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2944
Polymers19,3531
Non-polymers9423
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-20 kcal/mol
Surface area7990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.105, 40.324, 52.292
Angle α, β, γ (deg.)90, 100.95, 90
Int Tables number4
Space group name H-MP1211

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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.: 1
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.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-NZ6 / 1-[6-[4-(5-chloranyl-6-methyl-1~{H}-indazol-4-yl)-5-methyl-3-phenyl-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]propan-1-one / [6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one (precursor)


Mass: 473.997 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28ClN5O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.47 Å3/Da / Density % sol: 50.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 25% PEG 3350, 0.1 M sodium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.0000323 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0000323 Å / Relative weight: 1
ReflectionResolution: 1.49→45.27 Å / Num. obs: 18097 / % possible obs: 78.8 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 13.5
Reflection shellResolution: 1.49→1.67 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.316 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 905 / % possible all: 32.4

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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: 7r0q

7r0q


Resolution: 1.8→37.69 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.14 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.136 / SU Rfree Cruickshank DPI: 0.131
RfactorNum. reflection% reflectionSelection details
Rfree0.2151 773 -RANDOM
Rwork0.1755 ---
obs0.1774 15361 86.8 %-
Displacement parametersBiso mean: 19.6 Å2
Baniso -1Baniso -2Baniso -3
1-1.3731 Å20 Å2-0.5904 Å2
2---0.8403 Å20 Å2
3----0.5328 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.8→37.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1336 0 63 188 1587
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081446HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.931968HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d514SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes246HARMONIC5
X-RAY DIFFRACTIONt_it1446HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion186SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1431SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion14.68
LS refinement shellResolution: 1.8→1.82 Å
RfactorNum. reflection% reflection
Rfree0.2648 22 -
Rwork0.2208 --
obs0.2235 405 63.21 %
Refinement TLS params.Origin x: 4.0549 Å / Origin y: 8.8246 Å / Origin z: 14.453 Å
111213212223313233
T0.0225 Å20.0123 Å2-0.0086 Å2--0.0344 Å20.0033 Å2---0.0217 Å2
L0.1051 °20.1801 °2-0.0511 °2-0.684 °20.1901 °2--1.0736 °2
S-0.0137 Å °0.0832 Å °0.1287 Å °0.0832 Å °-0.0045 Å °0.0579 Å °0.1287 Å °0.0579 Å °0.0183 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 167
2X-RAY DIFFRACTION1{ A|* }A1001

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