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- PDB-6tam: X-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQ... -

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Basic information

Entry
Database: PDB / ID: 6tam
TitleX-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQUINOLINONE INHIBITOR (COMPOUND 3)
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / INHIBITOR / COVALENT BINDING
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
GUANOSINE-5'-DIPHOSPHATE / Chem-MZQ / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsFriberg, A. / Nguyen, D.
CitationJournal: Chemmedchem / Year: 2020
Title: Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.
Authors: Mortier, J. / Friberg, A. / Badock, V. / Moosmayer, D. / Schroeder, J. / Steigemann, P. / Siegel, F. / Gradl, S. / Bauser, M. / Hillig, R.C. / Briem, H. / Eis, K. / Bader, B. / Nguyen, D. / Christ, C.D.
History
DepositionOct 30, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 3, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)20,2034
Polymers19,3531
Non-polymers8503
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-19 kcal/mol
Surface area8310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.144, 58.522, 66.141
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


Mass: 19352.785 Da / Num. of mol.: 1 / Mutation: G12C, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Details: Protein covalently modified at G12C / 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.: 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-MZQ / 7-[2,4-bis(fluoranyl)phenyl]-3-[(3~{R})-1-propanoylpyrrolidin-3-yl]-4~{H}-isoquinolin-1-one


Mass: 382.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F2N2O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Nonpolymer detailsFIRST CRYSTAL STRUCTURE IN THE ISOQUINOLINONE SERIES. SWITCH II CONFORMATION ONLY TO BE ANALYZED ...FIRST CRYSTAL STRUCTURE IN THE ISOQUINOLINONE SERIES. SWITCH II CONFORMATION ONLY TO BE ANALYZED WITH CAUTION, DENSITY HERE IS VERY WEAK (I.E. HIGH B-FACTORS). COMPOUND IS WELL-DEFINED BY ELECTRON DENSITY. CORE IN COMPLETELY DIFFERENT ORIENTATION THAN THAT OF ARS-COMPOUNDS. AMIDE OF ISOQUINOLINONE EXHIBIT TWO HYDROGEN BONDS TO THE BACKBONE OF GLY10. TERMINAL PHENYL GROUP IN A SIMILAR POSITION AS FOUND IN ARS-1620.

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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: 2.06 Å3/Da / Density % sol: 40.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.9 / Details: 100 mM MES pH 6.9 and 34% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2018
RadiationMonochromator: KMC-1 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.64→50 Å / Num. obs: 20063 / % possible obs: 99.2 % / Redundancy: 12.8 % / Biso Wilson estimate: 34.2 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.0071 / Net I/σ(I): 20.1
Reflection shellResolution: 1.64→1.74 Å / Redundancy: 11.8 % / Mean I/σ(I) obs: 2.17 / Num. unique obs: 3072 / CC1/2: 0.818 / Rrim(I) all: 0.991 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.64→43.83 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.963 / SU B: 4.198 / SU ML: 0.07 / Cross valid method: THROUGHOUT / ESU R: 0.102 / ESU R Free: 0.096 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20053 1001 5 %RANDOM
Rwork0.1742 ---
obs0.17549 19061 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.391 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å2-0 Å2-0 Å2
2---0.64 Å20 Å2
3---0.83 Å2
Refinement stepCycle: LAST / Resolution: 1.64→43.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1359 0 57 125 1541
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0131478
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171338
X-RAY DIFFRACTIONr_angle_refined_deg1.4761.7142013
X-RAY DIFFRACTIONr_angle_other_deg1.3541.6173114
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1745179
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.01223.07778
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.95615260
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.568159
X-RAY DIFFRACTIONr_chiral_restr0.0640.2193
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021669
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02306
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_it0.9872.157704
X-RAY DIFFRACTIONr_mcbond_other0.9882.157703
X-RAY DIFFRACTIONr_mcangle_it1.7073.232887
X-RAY DIFFRACTIONr_mcangle_other1.7063.232888
X-RAY DIFFRACTIONr_scbond_it1.1842.365774
X-RAY DIFFRACTIONr_scbond_other1.1852.364773
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9133.4781127
X-RAY DIFFRACTIONr_long_range_B_refined4.626.1281708
X-RAY DIFFRACTIONr_long_range_B_other4.54725.751690
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.64→1.682 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 70 -
Rwork0.29 1247 -
obs--89.59 %
Refinement TLS params.Method: refined / Origin x: 7.0484 Å / Origin y: 0.4969 Å / Origin z: 6.8961 Å
111213212223313233
T0.0077 Å20.0123 Å20.001 Å2-0.0606 Å20.0038 Å2--0.0006 Å2
L1.061 °2-0.102 °2-0.0985 °2-1.3886 °2-0.2631 °2--1.5427 °2
S0.0501 Å °0.0497 Å °-0.0033 Å °-0.0273 Å °-0.0627 Å °-0.0222 Å °0.075 Å °0.025 Å °0.0125 Å °

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