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- PDB-5v9o: KRAS G12C inhibitor -

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Basic information

Entry
Database: PDB / ID: 5v9o
TitleKRAS G12C inhibitor
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE inhibitor / KRAS mutant inhibitor / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / RAF activation / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / 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 / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 domain 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-91G / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 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 / struct_conn_type
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.pdbx_value_order / _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
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2744
Polymers19,2461
Non-polymers1,0293
Water4,143230
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.159, 90.159, 90.159
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number195
Space group name H-MP23
Components on special symmetry positions
IDModelComponents
11A-510-

HOH

21A-523-

HOH

31A-529-

HOH

41A-530-

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.: 1
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.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-91G / N~3~-[6-chloro-7-(3-hydroxynaphthalen-1-yl)-4-(4-propanoylpiperazin-1-yl)quinazolin-2-yl]-N,N-dimethyl-beta-alaninamide


Mass: 561.074 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H33ClN6O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.18 Å3/Da / Density % sol: 61.35 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 9 / Details: 0.1M Tris pH9.0, ammonium sulfate 1.6M

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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: 1.56→50 Å / Num. obs: 35091 / % possible obs: 100 % / Redundancy: 31.8 % / Biso Wilson estimate: 13.88 Å2 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.014 / Rrim(I) all: 0.079 / Χ2: 1.044 / Net I/σ(I): 5.7 / Num. measured all: 1114863
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.56-1.59192.19217640.5110.5092.2521.04100
1.59-1.6226.62.06817140.6550.4062.1081.041100
1.62-1.6530.91.73717400.7780.3171.7661.048100
1.65-1.6829.81.51817570.8150.2821.5441.057100
1.68-1.7232.71.24316920.8980.221.2621.055100
1.72-1.76340.99417560.9340.1731.0091.072100
1.76-1.833.90.83517360.9510.1450.8481.076100
1.8-1.8533.60.63617550.9660.1110.6461.071100
1.85-1.933.10.49617430.9810.0870.5041.098100
1.9-1.9732.30.34417250.9910.0610.3491.094100
1.97-2.0430.10.25517370.9940.0470.261.092100
2.04-2.1234.50.19517290.9970.0340.1971.092100
2.12-2.2134.20.15517690.9980.0270.1571.092100
2.21-2.3333.90.12317430.9990.0210.1251.09100
2.33-2.4833.20.10117400.9990.0180.1021.036100
2.48-2.6731.10.07717800.9990.0140.0781.021100
2.67-2.94350.06176710.010.0611.009100
2.94-3.3633.80.043178410.0070.0430.977100
3.36-4.2331.60.033178510.0060.0340.918100
4.23-50320.03187510.0050.0310.90899.9

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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: 1.56→45.08 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1986 1982 5.77 %
Rwork0.1804 32387 -
obs0.1815 34369 97.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 85.66 Å2 / Biso mean: 20.8806 Å2 / Biso min: 6.48 Å2
Refinement stepCycle: final / Resolution: 1.56→45.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1343 0 69 230 1642
Biso mean--18.18 32.4 -
Num. residues----168
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061443
X-RAY DIFFRACTIONf_angle_d1.0191957
X-RAY DIFFRACTIONf_chiral_restr0.054212
X-RAY DIFFRACTIONf_plane_restr0.006247
X-RAY DIFFRACTIONf_dihedral_angle_d19.567861
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 (%)
1.5596-1.59860.2843980.30351730182873
1.5986-1.64180.28261440.2532286243098
1.6418-1.69010.22641410.223223312472100
1.6901-1.74470.2151380.205523152453100
1.7447-1.8070.21671430.191423472490100
1.807-1.87940.21361480.186723482496100
1.8794-1.96490.19581450.175923462491100
1.9649-2.06850.2031410.172423412482100
2.0685-2.19810.21141450.16723712516100
2.1981-2.36780.18441440.167123472491100
2.3678-2.60610.20771420.172523602502100
2.6061-2.98310.20661470.196523852532100
2.9831-3.75810.18571500.159823962546100
3.7581-45.09830.16561560.169324842640100

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