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- PDB-9bi2: Crystal structure of GMPPNP bound KRAS G12C in complex with CYPA ... -

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Basic information

Entry
Database: PDB / ID: 9bi2
TitleCrystal structure of GMPPNP bound KRAS G12C in complex with CYPA and RMC-7977
Components
  • Isoform 2B of GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN / GTPase SIGNALING PROTEIN Isomerase
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / negative regulation of viral life cycle / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / negative regulation of viral life cycle / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / forebrain astrocyte development / Basigin interactions / protein peptidyl-prolyl isomerization / negative regulation of epithelial cell differentiation / cyclosporin A binding / type I pneumocyte differentiation / Minus-strand DNA synthesis / Plus-strand DNA synthesis / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Uncoating of the HIV Virion / Rac protein signal transduction / Early Phase of HIV Life Cycle / Integration of provirus / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / APOBEC3G mediated resistance to HIV-1 infection / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / viral release from host cell / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of protein phosphorylation / Calcineurin activates NFAT / 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 / Binding and entry of HIV virion / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / positive regulation of viral genome replication / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / activation of protein kinase B activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / neutrophil chemotaxis / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / peptidyl-prolyl cis-trans isomerase activity / small monomeric GTPase / negative regulation of protein kinase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / positive regulation of protein secretion / peptidylprolyl isomerase / FCERI mediated MAPK activation / RAF activation
Similarity search - Function
Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site / Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases ...Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site / Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / 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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / : / GTPase KRas / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsPourfarjam, Y. / Goldgur, Y. / Cuevas-Navarro, A. / Lito, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nature / Year: 2025
Title: Pharmacological restoration of GTP hydrolysis by mutant RAS.
Authors: Cuevas-Navarro, A. / Pourfarjam, Y. / Hu, F. / Rodriguez, D.J. / Vides, A. / Sang, B. / Fan, S. / Goldgur, Y. / de Stanchina, E. / Lito, P.
History
DepositionApr 22, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2025Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
B: Peptidyl-prolyl cis-trans isomerase A
D: Peptidyl-prolyl cis-trans isomerase A
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,76010
Polymers74,9374
Non-polymers2,8236
Water6,323351
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.128, 81.549, 128.179
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ACBD

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


Mass: 19374.902 Da / Num. of mol.: 2 / Mutation: G12C
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
#2: Protein Peptidyl-prolyl cis-trans isomerase A / PPIase A / Cyclophilin A / Cyclosporin A-binding protein / Rotamase A


Mass: 18093.555 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIA, CYPA / Production host: Escherichia coli (E. coli) / References: UniProt: P62937, peptidylprolyl isomerase

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Non-polymers , 4 types, 357 molecules

#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ZNI / (1R,5S,6r)-N-[(1P,7S,9S,13S,20M)-20-{5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-21-ethyl-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1~2,5~.1~9,13~.0~22,26~]octacosa-1(24),2,5(28),19,22,25-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide / RMC-7977


Mass: 865.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 351 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.27 Å3/Da / Density % sol: 45.84 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / Details: 100 mM Tris-HCl pH 8.5, 24% PEG 10000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 14, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.15→29.82 Å / Num. obs: 37628 / % possible obs: 99.9 % / Redundancy: 7.4 % / Rrim(I) all: 0.199 / Net I/σ(I): 14.24
Reflection shellResolution: 2.15→2.19 Å / Num. unique obs: 1111 / Rrim(I) all: 0.767

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→29.82 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2359 1842 4.9 %
Rwork0.1852 --
obs0.1877 37554 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.15→29.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5190 0 190 351 5731
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d0.69
X-RAY DIFFRACTIONf_dihedral_angle_d13.757770
X-RAY DIFFRACTIONf_chiral_restr0.045790
X-RAY DIFFRACTIONf_plane_restr0.004947
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.210.31431330.24832599X-RAY DIFFRACTION96
2.21-2.280.29611550.23732679X-RAY DIFFRACTION100
2.28-2.350.27821350.21612730X-RAY DIFFRACTION100
2.35-2.430.28121250.20782751X-RAY DIFFRACTION100
2.43-2.530.24441370.20242723X-RAY DIFFRACTION100
2.53-2.650.33351340.1982715X-RAY DIFFRACTION100
2.65-2.790.24531580.1962725X-RAY DIFFRACTION100
2.79-2.960.25941440.19312750X-RAY DIFFRACTION100
2.96-3.190.23861360.18122755X-RAY DIFFRACTION100
3.19-3.510.20891580.16342759X-RAY DIFFRACTION100
3.51-4.020.18571490.14862768X-RAY DIFFRACTION100
4.02-5.050.18241400.14982804X-RAY DIFFRACTION100
5.06-29.820.25911380.21172954X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -12.9117 Å / Origin y: 20.0246 Å / Origin z: -21.9108 Å
111213212223313233
T0.1305 Å20.0049 Å2-0.0215 Å2-0.1358 Å2-0.0022 Å2--0.1478 Å2
L0.4197 °2-0.1397 °2-0.0814 °2-0.4512 °2-0.0774 °2--0.5228 °2
S0.0898 Å °0.0779 Å °-0.0402 Å °-0.0956 Å °-0.0279 Å °0.0458 Å °0.0288 Å °-0.0155 Å °-0.0598 Å °
Refinement TLS groupSelection details: all

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