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- PDB-8afd: CRYSTAL STRUCTURE OF BIT-BLOCKED KRAS-G12V-S39C IN COMPLEX WITH C... -

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Basic information

Entry
Database: PDB / ID: 8afd
TitleCRYSTAL STRUCTURE OF BIT-BLOCKED KRAS-G12V-S39C IN COMPLEX WITH COMPOUND 20a
ComponentsGTPase KRas
KeywordsONCOPROTEIN / KRAS / GTPase / G12C / Complex / Inhibitor
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 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / 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 / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / 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 / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / 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
1H-benzimidazol-2-ylmethanethiol / GUANOSINE-5'-DIPHOSPHATE / Chem-LXU / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.633 Å
AuthorsBoettcher, J. / Kessler, D.
Funding support Austria, 1items
OrganizationGrant numberCountry
Other private Austria
CitationJournal: J.Med.Chem. / Year: 2022
Title: Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS G12C Inhibitor.
Authors: Broker, J. / Waterson, A.G. / Smethurst, C. / Kessler, D. / Bottcher, J. / Mayer, M. / Gmaschitz, G. / Phan, J. / Little, A. / Abbott, J.R. / Sun, Q. / Gmachl, M. / Rudolph, D. / Arnhof, H. ...Authors: Broker, J. / Waterson, A.G. / Smethurst, C. / Kessler, D. / Bottcher, J. / Mayer, M. / Gmaschitz, G. / Phan, J. / Little, A. / Abbott, J.R. / Sun, Q. / Gmachl, M. / Rudolph, D. / Arnhof, H. / Rumpel, K. / Savarese, F. / Gerstberger, T. / Mischerikow, N. / Treu, M. / Herdeis, L. / Wunberg, T. / Gollner, A. / Weinstabl, H. / Mantoulidis, A. / Kramer, O. / McConnell, D.B. / W Fesik, S.
History
DepositionJul 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 2.0Nov 23, 2022Group: Atomic model / Database references
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / citation / citation_author
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,71318
Polymers77,4844
Non-polymers3,23014
Water7,098394
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3545
Polymers19,3711
Non-polymers9834
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3545
Polymers19,3711
Non-polymers9834
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0034
Polymers19,3711
Non-polymers6323
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0034
Polymers19,3711
Non-polymers6323
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)94.891, 98.614, 148.116
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 19370.891 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116, small monomeric GTPase

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Non-polymers , 5 types, 408 molecules

#2: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical
ChemComp-2XO / 1H-benzimidazol-2-ylmethanethiol


Mass: 164.228 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H8N2S
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-LXU / (4~{S})-4-[3-(4-aminophenyl)-1,2,4-oxadiazol-5-yl]-2-azanyl-4-methyl-6,7-dihydro-5~{H}-1-benzothiophene-3-carbonitrile


Mass: 351.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17N5OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 394 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.24 Å3/Da / Density % sol: 44.99 %
Crystal growTemperature: 297 K / Method: vapor diffusion / Details: 100mM PCB pH 5.9, 20% PEG 1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999882 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999882 Å / Relative weight: 1
ReflectionResolution: 1.633→74.058 Å / Num. obs: 47959 / % possible obs: 55.7 % / Redundancy: 12.6 % / Biso Wilson estimate: 23.05 Å2 / Rmerge(I) obs: 0.118 / Rsym value: 0.118 / Net I/σ(I): 12.1
Reflection shellResolution: 1.633→1.853 Å / Redundancy: 9.4 % / Rmerge(I) obs: 1.187 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 2399 / Rsym value: 1.187 / % possible all: 8.9

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (3-FEB-2022)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7U90

7u90
PDB Unreleased entry


Resolution: 1.633→32.56 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.896 / SU R Cruickshank DPI: 0.563 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.229 / SU Rfree Blow DPI: 0.184 / SU Rfree Cruickshank DPI: 0.182
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2654 1663 3.47 %RANDOM
Rwork0.2313 ---
obs0.2325 47945 55.7 %-
Displacement parametersBiso max: 77.58 Å2 / Biso mean: 29.35 Å2 / Biso min: 10.22 Å2
Baniso -1Baniso -2Baniso -3
1-1.4223 Å20 Å20 Å2
2--2.2701 Å20 Å2
3----3.6923 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 1.633→32.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5179 0 210 394 5783
Biso mean--25.84 34.95 -
Num. residues----650
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3281SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1811HARMONIC5
X-RAY DIFFRACTIONt_it5274HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion720SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies2HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8586SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d10734HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg19337HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion15.34
LS refinement shellResolution: 1.633→1.79 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3917 39 4.07 %
Rwork0.2949 920 -
obs--4.76 %

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