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- PDB-4nmm: Crystal Structure of a G12C Oncogenic Variant of Human KRas Bound... -

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Basic information

Entry
Database: PDB / ID: 4nmm
TitleCrystal Structure of a G12C Oncogenic Variant of Human KRas Bound to a Novel GDP Competitive Covalent Inhibitor
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Small GTPase / GDP bound / oncogenic mutation / covalent inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / 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 / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / 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 / 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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-Y9Z / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsHunter, J.C. / Gurbani, D. / Lim, S.M. / Westover, K.D.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2014
Title: In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C.
Authors: Hunter, J.C. / Gurbani, D. / Ficarro, S.B. / Carrasco, M.A. / Lim, S.M. / Choi, H.G. / Xie, T. / Marto, J.A. / Chen, Z. / Gray, N.S. / Westover, K.D.
History
DepositionNov 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)19,9283
Polymers19,3751
Non-polymers5532
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.088, 42.022, 91.159
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / GTPase KRas / N-terminally processed


Mass: 19374.902 Da / Num. of mol.: 1 / Fragment: UNP residues 1-169 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pJexpress401 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: P01116, small monomeric GTPase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-Y9Z / 5'-O-[(S)-{[(S)-[2-(acetylamino)ethoxy](hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]guanosine


Mass: 528.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H22N6O12P2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE UNREACTED INHIBITOR IS 5'-O-[(S)-{[(S)-{2-[(CHLOROCARBONYL)AMINO]ETHOXY}(HYDROXY)PHOSPHORYL] ...THE UNREACTED INHIBITOR IS 5'-O-[(S)-{[(S)-{2-[(CHLOROCARBONYL)AMINO]ETHOXY}(HYDROXY)PHOSPHORYL]OXY}(HYDROXY)PHOSPHORYL]GUANOSINE, THE CHLORO-ACETLY GROUP REACTS WITH CYS A12 RESIDUE ON THE PROTEIN TO FORM A THIO-ETHER LINKAGE BETWEEN C13 ATOM OF Y9Z AND SG ATOM of CYS A12 WITH THE CHLORINE ACTING AS A LEAVING GROUP. LIGAND Y9Z REPRESENT THE REACTED/BOUND FORM OF THE INHIBITOR.
Sequence detailsTHE SEQUENCE MATCHES UNIPROT ENTRY P01116, ISOFORM 2B WITH IDENTIFIER P01116-2

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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: 1.93 Å3/Da / Density % sol: 36.34 %
Crystal growTemperature: 277 K / pH: 4
Details: 0.2M MMT pH4.0, 28% PEG 6,000, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97921
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 12, 2013
RadiationMonochromator: ROSENBAUM-ROCK HIGH-RESOLUTION DOUBLE-CRYSTAL MONOCHROMATOR
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97921 Å / Relative weight: 1
ReflectionResolution: 1.89→50 Å / Num. obs: 12363 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 5.8 % / Biso Wilson estimate: 23.29 Å2 / Rmerge(I) obs: 0.126 / Net I/σ(I): 14.469
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.883 / Mean I/σ(I) obs: 2.036 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
REFMAC5.8.0049refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4EPV

4epv


Resolution: 1.89→45.58 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.931 / SU B: 4.717 / SU ML: 0.133 / Cross valid method: THROUGHOUT / ESU R: 0.185 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.237 615 5 %RANDOM
Rwork0.184 ---
obs0.186 11695 --
all-12363 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.81 Å2
Baniso -1Baniso -2Baniso -3
1--2.46 Å20 Å20 Å2
2--3.17 Å20 Å2
3----0.71 Å2
Refinement stepCycle: LAST / Resolution: 1.89→45.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1357 0 35 125 1517
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0191419
X-RAY DIFFRACTIONr_bond_other_d0.0070.021332
X-RAY DIFFRACTIONr_angle_refined_deg1.3641.9921921
X-RAY DIFFRACTIONr_angle_other_deg0.7683.0013072
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0115171
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.22524.49369
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.00615255
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3141510
X-RAY DIFFRACTIONr_chiral_restr0.0750.2213
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021589
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02318
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1522.293683
X-RAY DIFFRACTIONr_mcbond_other2.1082.289680
X-RAY DIFFRACTIONr_mcangle_it2.9633.43851
X-RAY DIFFRACTIONr_mcangle_other2.9743.432851
X-RAY DIFFRACTIONr_scbond_it3.2572.77736
X-RAY DIFFRACTIONr_scbond_other3.2592.771734
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.144.0051068
X-RAY DIFFRACTIONr_long_range_B_refined6.81620.0841703
X-RAY DIFFRACTIONr_long_range_B_other6.72319.7491658
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.89→1.94 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.26 28 -
Rwork0.306 598 -
obs--67.75 %

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