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- PDB-5v9l: KRAS G12C in bound to quinazoline based switch II pocket (SWIIP) ... -

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Basic information

Entry
Database: PDB / ID: 5v9l
TitleKRAS G12C in bound to quinazoline based switch II pocket (SWIIP) binder
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE inhibitor / KRAS mutant 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 / 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 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-91D / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.981 Å
AuthorsWestover, K. / Lu, J.
CitationJournal: Cell Chem Biol / Year: 2017
Title: Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.
Authors: Zeng, M. / Lu, J. / Li, L. / Feru, F. / Quan, C. / Gero, T.W. / Ficarro, S.B. / Xiong, Y. / Ambrogio, C. / Paranal, R.M. / Catalano, M. / Shao, J. / Wong, K.K. / Marto, J.A. / Fischer, E.S. ...Authors: Zeng, M. / Lu, J. / Li, L. / Feru, F. / Quan, C. / Gero, T.W. / Ficarro, S.B. / Xiong, Y. / Ambrogio, C. / Paranal, R.M. / Catalano, M. / Shao, J. / Wong, K.K. / Marto, J.A. / Fischer, E.S. / Janne, P.A. / Scott, D.A. / Westover, K.D. / Gray, N.S.
History
DepositionMar 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 30, 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

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,67912
Polymers57,7373
Non-polymers2,9429
Water4,324240
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2264
Polymers19,2461
Non-polymers9813
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2264
Polymers19,2461
Non-polymers9813
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2264
Polymers19,2461
Non-polymers9813
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.062, 85.062, 130.542
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Components on special symmetry positions
IDModelComponents
11A-370-

HOH

21A-374-

HOH

31B-398-

HOH

41C-367-

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.: 3
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 / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / 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.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-91D / N~3~-[6-chloro-7-(2-fluorophenyl)-4-(4-propanoylpiperazin-1-yl)quinazolin-2-yl]-N,N-dimethyl-beta-alaninamide


Mass: 513.007 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H30ClFN6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 240 / 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: 47.91 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 7.1
Details: 1.6M sodium phosphate monobasic monohydrate, potassium phosphate dibasic pH7.1

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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: Feb 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.98→50 Å / Num. obs: 37066 / % possible obs: 99.7 % / Redundancy: 8.1 % / Biso Wilson estimate: 23.5 Å2 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.027 / Rrim(I) all: 0.076 / Χ2: 0.939 / Net I/σ(I): 7.5 / Num. measured all: 298646
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.98-2.0161.003183118310.6980.4411.0980.94599
2.01-2.056.70.93918340.7360.3891.0190.95699.7
2.05-2.097.30.80218420.840.3160.8640.995100
2.09-2.137.90.7118820.8890.2680.760.935100
2.13-2.188.20.62418490.8910.230.6660.91899.9
2.18-2.238.20.4818450.9440.1760.5130.92799.9
2.23-2.297.90.39618480.9530.1490.4240.995100
2.29-2.3580.32318560.970.1210.3460.885100
2.35-2.428.80.29218570.9780.1030.310.894100
2.42-2.498.70.23918690.9830.0850.2540.88999.9
2.49-2.588.60.18918550.9870.0670.2010.856100
2.58-2.698.50.15218390.9870.0550.1620.859100
2.69-2.817.80.12418440.9890.0470.1330.87199.8
2.81-2.968.60.09618590.9910.0350.1030.86899.8
2.96-3.148.80.07118660.9920.0250.0750.84999.9
3.14-3.398.70.05518580.9940.020.0590.88799.7
3.39-3.737.90.04518440.9930.0170.0480.90799.7
3.73-4.268.70.04118650.9940.0150.0440.98399.1
4.26-5.3780.0418440.9940.0150.0431.07198.3
5.37-507.90.04618790.9950.0180.0491.35298.6

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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: 1.981→48.853 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 23.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2255 1994 5.79 %
Rwork0.1709 32417 -
obs0.1741 34411 92.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 107.04 Å2 / Biso mean: 34.0531 Å2 / Biso min: 8.81 Å2
Refinement stepCycle: final / Resolution: 1.981→48.853 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4041 0 195 240 4476
Biso mean--31.17 33.98 -
Num. residues----507
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084342
X-RAY DIFFRACTIONf_angle_d0.9785885
X-RAY DIFFRACTIONf_chiral_restr0.054637
X-RAY DIFFRACTIONf_plane_restr0.007749
X-RAY DIFFRACTIONf_dihedral_angle_d16.6872591
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 (%)
1.981-2.03050.3312880.23691442153058
2.0305-2.08540.30661080.22751761186971
2.0854-2.14680.28961260.20952019214581
2.1468-2.21610.261400.20352273241392
2.2161-2.29530.27551540.18692480263498
2.2953-2.38720.23641520.179624812633100
2.3872-2.49580.24461530.17425162669100
2.4958-2.62740.2571500.178524812631100
2.6274-2.7920.23081540.18324842638100
2.792-3.00750.24451500.183125092659100
3.0075-3.31010.24971590.168824912650100
3.3101-3.7890.2111480.151325122660100
3.789-4.77310.14351560.13522476263299
4.7731-48.8680.221560.17092492264898

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