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- PDB-5kyk: Covalent GTP-competitive inhibitors of KRAS G12C: Guanosine bisph... -

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Basic information

Entry
Database: PDB / ID: 5kyk
TitleCovalent GTP-competitive inhibitors of KRAS G12C: Guanosine bisphosphonate Analogs
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE inhibitor / KRAS / Cancer / covalent inhibitor / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / 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 / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / GDP binding / 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 / 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 / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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-6ZD / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.702 Å
AuthorsXiong, Y. / Lu, J. / Hunter, J. / Li, L. / Scott, D. / Manandhar, A. / Gondi, S. / Westover, K.D. / Gray, N.S.
Funding support United States, 1items
OrganizationGrant numberCountry
V Scholar ResearchWel I-1829 United States
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Covalent Guanosine Mimetic Inhibitors of G12C KRAS.
Authors: Xiong, Y. / Lu, J. / Hunter, J. / Li, L. / Scott, D. / Choi, H.G. / Lim, S.M. / Manandhar, A. / Gondi, S. / Sim, T. / Westover, K.D. / Gray, N.S.
History
DepositionJul 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)59,4176
Polymers57,7373
Non-polymers1,6803
Water54030
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8062
Polymers19,2461
Non-polymers5601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8062
Polymers19,2461
Non-polymers5601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8062
Polymers19,2461
Non-polymers5601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)114.830, 66.155, 98.006
Angle α, β, γ (deg.)90.000, 112.980, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-307-

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 / Fragment: UNP residues 1-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116
#2: Chemical ChemComp-6ZD / 5'-O-[(R)-[({2-[(chloroacetyl)amino]ethyl}sulfamoyl)methyl](hydroxy)phosphoryl]guanosine


Mass: 559.876 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C15H23ClN7O10PS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 3.01 Å3/Da / Density % sol: 59.19 %
Crystal growTemperature: 293 K / Method: evaporation
Details: Protein was purified in buffer: 20 mM Hepes pH 8.0, 150 mM NaCl, 5 mM MgCl2 and 0.5 mM DTT. Crystals grew in five days at room temperature from hanging vapor diffusion drops with following ...Details: Protein was purified in buffer: 20 mM Hepes pH 8.0, 150 mM NaCl, 5 mM MgCl2 and 0.5 mM DTT. Crystals grew in five days at room temperature from hanging vapor diffusion drops with following condition: 0.1 M Citric acid pH 4.0, 20% PEG 3350. Crystals were cryoprotected in mother liquid with 40% PEG 3350 and flash frozen in liquid nitrogen.

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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: Jun 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. obs: 19876 / % possible obs: 99.8 % / Redundancy: 6.3 % / Biso Wilson estimate: 78.16 Å2 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.033 / Rrim(I) all: 0.078 / Χ2: 1.193 / Net I/σ(I): 9.3 / Num. measured all: 126113
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique allCC1/2Rpim(I) allΧ2% possible allRmerge(I) obsRrim(I) all
2.65-2.74.69310.4590.6960.97998.1
2.7-2.745.310120.7240.4960.9599.7
2.74-2.85.89790.720.4390.9531000.982
2.8-2.856.29490.8350.3360.9631000.7740.844
2.85-2.926.410220.890.2820.9671000.6590.718
2.92-2.986.59760.9220.211.0121000.4980.541
2.98-3.066.69940.9140.2041.0421000.4870.528
3.06-3.146.710070.970.1511.0861000.3610.391
3.14-3.236.79880.9770.1231.1211000.2940.319
3.23-3.346.79640.9850.0831.1451000.1980.215
3.34-3.466.710150.9830.0771.3081000.1830.199
3.46-3.66.79830.9920.0581.2851000.1390.151
3.6-3.766.610040.9950.0461.4311000.1090.119
3.76-3.966.69950.9970.0351.4661000.0820.089
3.96-4.216.79930.9980.0261.1811000.0620.067
4.21-4.536.610050.9970.0261.3321000.0620.067
4.53-4.996.610070.9970.0251.1441000.0590.064
4.99-5.716.59960.9970.0261.6491000.060.066
5.71-7.196.310190.9980.0191.2971000.0450.049
7.19-506.210370.9980.0171.338990.0390.043

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NMM

4nmm


Resolution: 2.702→43.741 Å / SU ML: 0.49 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 38.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3144 923 4.94 %
Rwork0.2673 17750 -
obs0.2695 18673 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 224.95 Å2 / Biso mean: 105.8117 Å2 / Biso min: 47.76 Å2
Refinement stepCycle: final / Resolution: 2.702→43.741 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3837 0 102 30 3969
Biso mean--86.94 71.04 -
Num. residues----483
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024005
X-RAY DIFFRACTIONf_angle_d0.4785391
X-RAY DIFFRACTIONf_chiral_restr0.039602
X-RAY DIFFRACTIONf_plane_restr0.003686
X-RAY DIFFRACTIONf_dihedral_angle_d14.0082384
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7024-2.84480.43521230.36612457258098
2.8448-3.0230.43831300.336725492679100
3.023-3.25640.4081310.32725152646100
3.2564-3.5840.32281300.289325512681100
3.584-4.10220.28141370.260925562693100
4.1022-5.16710.25981330.233625412674100
5.1671-43.74720.32441390.255125812720100

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