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- PDB-5v71: KRAS G12C in bound to quinazoline based switch II pocket (SWIIP) ... -

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Basic information

Entry
Database: PDB / ID: 5v71
TitleKRAS G12C in bound to quinazoline based switch II pocket (SWIIP) binder
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE inhibitor / KRAS / covalent inhibitor / quinazoline based / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / SHC-mediated cascade:FGFR2 / 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 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / 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 / GDP binding / Signaling by BRAF and RAF1 fusions / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-8ZG / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.228 Å
AuthorsWestover, K. / Lu, J.
CitationJournal: Structure / Year: 2017
Title: KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry.
Authors: Lu, J. / Harrison, R.A. / Li, L. / Zeng, M. / Gondi, S. / Scott, D. / Gray, N.S. / Engen, J.R. / Westover, K.D.
History
DepositionMar 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 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
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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_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.ptnr1_auth_asym_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_asym_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
C: GTPase KRas
D: GTPase KRas
E: GTPase KRas
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,67324
Polymers115,4746
Non-polymers5,19818
Water6,720373
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1124
Polymers19,2461
Non-polymers8663
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.933, 84.933, 130.785
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number143
Space group name H-MP3
Components on special symmetry positions
IDModelComponents
11A-378-

HOH

21B-361-

HOH

31D-379-

HOH

41E-340-

HOH

51F-357-

HOH

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Components

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


Mass: 19245.723 Da / Num. of mol.: 6 / Fragment: UNP residues 1-168 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P01116
#2: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 6 / 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.: 6 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-8ZG / 1-{4-[6-chloro-7-(2-fluorophenyl)quinazolin-4-yl]piperazin-1-yl}propan-1-one


Mass: 398.861 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C21H20ClFN4O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 373 / Source method: isolated from a natural source / Formula: H2O

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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: 2.36 Å3/Da / Density % sol: 47.85 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 6.9
Details: 1.8M sodium phosphate monobasic monohydrate, potassium phosphate dibasic pH6.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.23→50 Å / Num. obs: 51433 / % possible obs: 99.8 % / Redundancy: 7.8 % / Biso Wilson estimate: 31.44 Å2 / Rmerge(I) obs: 0.183 / Rpim(I) all: 0.068 / Rrim(I) all: 0.195 / Χ2: 0.961 / Net I/σ(I): 3.6 / Num. measured all: 399357
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.23-2.2751.53625690.4760.7061.6970.96799.7
2.27-2.315.51.36925670.6130.6011.50.964100
2.31-2.355.91.34225700.6620.5671.460.937100
2.35-2.46.31.30225790.6770.5381.4120.925100
2.4-2.456.81.23725920.7470.4961.3350.948100
2.45-2.517.11.20625460.7460.4771.2990.953100
2.51-2.577.41.05826090.8240.4121.1370.943100
2.57-2.647.30.97125600.8410.3821.0450.96499.7
2.64-2.727.90.88325420.8860.3330.9450.97198.7
2.72-2.818.80.7625650.9380.2710.8080.949100
2.81-2.918.90.6225400.9540.2210.6590.971100
2.91-3.038.80.47526320.9670.1690.5050.966100
3.03-3.168.80.34625780.9810.1230.3680.969100
3.16-3.338.60.26625590.9850.0960.2830.994100
3.33-3.547.90.19525480.9880.0730.2090.97599.1
3.54-3.819.20.15125640.9940.0520.160.999100
3.81-4.290.1125930.9960.0390.1170.987100
4.2-4.88.70.08225520.9970.0290.0870.992100
4.8-6.058.40.08325930.9970.030.0890.92499.7
6.05-508.70.0625750.9980.0220.0640.90899.8

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.22data extraction
HKL-3000data scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OBE

4obe


Resolution: 2.228→40.391 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 25.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.228 1976 4.37 %
Rwork0.1692 43222 -
obs0.1717 45198 87.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 134.43 Å2 / Biso mean: 41.4951 Å2 / Biso min: 11.56 Å2
Refinement stepCycle: final / Resolution: 2.228→40.391 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8082 0 342 374 8798
Biso mean--32.09 37.13 -
Num. residues----1014
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0098580
X-RAY DIFFRACTIONf_angle_d1.00311616
X-RAY DIFFRACTIONf_chiral_restr0.0541266
X-RAY DIFFRACTIONf_plane_restr0.0071476
X-RAY DIFFRACTIONf_dihedral_angle_d16.485118
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2284-2.28420.3353770.23831682175948
2.2842-2.34590.291850.21992032211757
2.3459-2.41490.2836960.22492337243366
2.4149-2.49290.28151240.22392713283777
2.4929-2.5820.28941410.21533061320287
2.582-2.68530.26261460.20573295344194
2.6853-2.80750.26681650.213535293694100
2.8075-2.95550.25441640.197735113675100
2.9555-3.14060.2441620.187235313693100
3.1406-3.3830.25881700.176435023672100
3.383-3.72320.22471560.15693495365199
3.7232-4.26140.20011640.133135203684100
4.2614-5.3670.17021650.123135203685100
5.367-40.39720.19171610.16053494365599

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