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- PDB-6gj8: CRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH BI 2852 -

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Basic information

Entry
Database: PDB / ID: 6gj8
TitleCRYSTAL STRUCTURE OF KRAS G12D (GPPCP) IN COMPLEX WITH BI 2852
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / KRAS 4B / K-RAS 2 / KI-RAS / C-K-RAS / C-KI-RAS / GTPASE KRAS
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-F0K / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsKessler, D. / Mcconnell, D.M. / Mantoulidis, A.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Science Fund854341 Austria
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Drugging an undruggable pocket on KRAS.
Authors: Kessler, D. / Gmachl, M. / Mantoulidis, A. / Martin, L.J. / Zoephel, A. / Mayer, M. / Gollner, A. / Covini, D. / Fischer, S. / Gerstberger, T. / Gmaschitz, T. / Goodwin, C. / Greb, P. / ...Authors: Kessler, D. / Gmachl, M. / Mantoulidis, A. / Martin, L.J. / Zoephel, A. / Mayer, M. / Gollner, A. / Covini, D. / Fischer, S. / Gerstberger, T. / Gmaschitz, T. / Goodwin, C. / Greb, P. / Haring, D. / Hela, W. / Hoffmann, J. / Karolyi-Oezguer, J. / Knesl, P. / Kornigg, S. / Koegl, M. / Kousek, R. / Lamarre, L. / Moser, F. / Munico-Martinez, S. / Peinsipp, C. / Phan, J. / Rinnenthal, J. / Sai, J. / Salamon, C. / Scherbantin, Y. / Schipany, K. / Schnitzer, R. / Schrenk, A. / Sharps, B. / Siszler, G. / Sun, Q. / Waterson, A. / Wolkerstorfer, B. / Zeeb, M. / Pearson, M. / Fesik, S.W. / McConnell, D.B.
History
DepositionMay 16, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 14, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 17, 2024Group: 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

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3204
Polymers19,2581
Non-polymers1,0623
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-14 kcal/mol
Surface area8180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.604, 116.842, 91.486
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-456-

HOH

21A-476-

HOH

31A-483-

HOH

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Components

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


Mass: 19257.668 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 (E. coli) / References: UniProt: P01116
#2: Chemical ChemComp-F0K / (3~{S})-3-[2-[[[1-[(1-methylimidazol-4-yl)methyl]indol-6-yl]methylamino]methyl]-1~{H}-indol-3-yl]-5-oxidanyl-2,3-dihydroisoindol-1-one


Mass: 516.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28N6O2
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.87 Å3/Da / Density % sol: 57.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 25% PEG3350, 0.2M ammonium sulfate and 0.1M bis-TRIS buffer at pH 6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Feb 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.65→36.03 Å / Num. obs: 23024 / % possible obs: 85.9 % / Redundancy: 5.8 % / Biso Wilson estimate: 14.91 Å2 / Rsym value: 0.039 / Net I/σ(I): 31.9
Reflection shellResolution: 1.65→1.709 Å

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EPV

4epv


Resolution: 1.65→36.03 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.099 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.11 / SU Rfree Blow DPI: 0.1 / SU Rfree Cruickshank DPI: 0.093
RfactorNum. reflection% reflectionSelection details
Rfree0.198 1155 5.02 %RANDOM
Rwork0.176 ---
obs0.177 23024 84.3 %-
Displacement parametersBiso mean: 15.51 Å2
Baniso -1Baniso -2Baniso -3
1--0.2398 Å20 Å20 Å2
2--0.2853 Å20 Å2
3----0.0455 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.65→36.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1349 0 72 234 1655
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0081486HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.932025HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d540SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes44HARMONIC2
X-RAY DIFFRACTIONt_gen_planes210HARMONIC5
X-RAY DIFFRACTIONt_it1486HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion16.49
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion189SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1926SEMIHARMONIC4
LS refinement shellResolution: 1.65→1.72 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2538 -3.77 %
Rwork0.2283 740 -
all0.2291 769 -
obs--23.4 %
Refinement TLS params.Method: refined / Origin x: 16.4026 Å / Origin y: 16.8011 Å / Origin z: -5.53 Å
111213212223313233
T-0.0325 Å2-0.0021 Å20.0028 Å2--0.0309 Å20.0029 Å2---0.0282 Å2
L0.5355 °2-0.3087 °20.1322 °2-0.7947 °20.1187 °2--0.7913 °2
S-0.0254 Å °0.003 Å °-0.0466 Å °0.1053 Å °0.0361 Å °0.0035 Å °0.0277 Å °0.0016 Å °-0.0107 Å °
Refinement TLS groupSelection details: { A|* }

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