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- PDB-9bg2: Tri-complex of Compound-10, KRAS G12V, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bg2
TitleTri-complex of Compound-10, KRAS G12V, and CypA
Components
  • GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN/INHIBITOR / inhibitor / complex / small GTPase / cancer / tri-complex / SIGNALING PROTEIN-INHIBITOR complex / SIGNALING PROTEIN
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: 1.64 Å
AuthorsTomlinson, A.C.A. / Bieder, R. / Chen, A. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers.
Authors: Cregg, J. / Edwards, A.V. / Chang, S. / Lee, B.J. / Knox, J.E. / Tomlinson, A.C.A. / Marquez, A. / Liu, Y. / Freilich, R. / Aay, N. / Wang, Y. / Jiang, L. / Jiang, J. / Wang, Z. / Flagella, ...Authors: Cregg, J. / Edwards, A.V. / Chang, S. / Lee, B.J. / Knox, J.E. / Tomlinson, A.C.A. / Marquez, A. / Liu, Y. / Freilich, R. / Aay, N. / Wang, Y. / Jiang, L. / Jiang, J. / Wang, Z. / Flagella, M. / Wildes, D. / Smith, J.A.M. / Singh, M. / Wang, Z. / Gill, A.L. / Koltun, E.S.
History
DepositionApr 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)77,56810
Polymers75,0494
Non-polymers2,5196
Water11,385632
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7845
Polymers37,5242
Non-polymers1,2593
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7845
Polymers37,5242
Non-polymers1,2593
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.360, 85.570, 127.330
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 2 types, 4 molecules ABCD

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


Mass: 19400.916 Da / Num. of mol.: 2
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: 18123.582 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, 638 molecules

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


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3
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-A1AOJ / (1S,2R)-N-[(1P,7S,9S,13S,20M)-21-ethyl-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-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]-2-methylcyclopropane-1-carboxamide (non-preferred name)


Mass: 712.901 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H48N6O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 632 / 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: 2.41 Å3/Da / Density % sol: 48.93 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 28% PEG 3350, 0.1M Bis Tris, pH 5.5, 150 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.95299 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jan 19, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95299 Å / Relative weight: 1
ReflectionResolution: 1.64→58.85 Å / Num. obs: 88855 / % possible obs: 99.29 % / Redundancy: 10.9 % / Biso Wilson estimate: 26.88 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1079 / Rpim(I) all: 0.03378 / Net I/σ(I): 11.23
Reflection shellResolution: 1.64→1.699 Å / Redundancy: 11.8 % / Rmerge(I) obs: 2.892 / Mean I/σ(I) obs: 0.95 / Num. unique obs: 8775 / CC1/2: 0.361 / CC star: 0.728 / Rpim(I) all: 0.8608 / % possible all: 99.35

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.64→58.85 Å / SU ML: 0.246 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.7943
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2283 4392 4.95 %
Rwork0.1996 84412 -
obs0.2011 88804 99.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.33 Å2
Refinement stepCycle: LAST / Resolution: 1.64→58.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5171 0 168 632 5971
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01065514
X-RAY DIFFRACTIONf_angle_d1.14217462
X-RAY DIFFRACTIONf_chiral_restr0.073797
X-RAY DIFFRACTIONf_plane_restr0.0111963
X-RAY DIFFRACTIONf_dihedral_angle_d14.2552082
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.64-1.660.36961490.33222738X-RAY DIFFRACTION98.97
1.66-1.680.37311510.3412804X-RAY DIFFRACTION99.6
1.68-1.70.36011260.33262806X-RAY DIFFRACTION99.49
1.7-1.720.42451290.33762807X-RAY DIFFRACTION99.26
1.72-1.740.37081440.31782790X-RAY DIFFRACTION99.59
1.74-1.770.36131440.28862745X-RAY DIFFRACTION99.38
1.77-1.790.28361560.26732824X-RAY DIFFRACTION99.77
1.79-1.820.29781190.25032811X-RAY DIFFRACTION99.69
1.82-1.850.2871410.2512801X-RAY DIFFRACTION99.56
1.85-1.880.30191480.26482771X-RAY DIFFRACTION99.02
1.88-1.910.34731400.31812685X-RAY DIFFRACTION96.35
1.91-1.940.36921220.34622718X-RAY DIFFRACTION94.98
1.94-1.980.30511570.2442750X-RAY DIFFRACTION99.73
1.98-2.020.24271550.23432828X-RAY DIFFRACTION100
2.02-2.070.30391440.24112808X-RAY DIFFRACTION99.29
2.07-2.110.27221380.23922787X-RAY DIFFRACTION98.98
2.11-2.170.27771470.20822817X-RAY DIFFRACTION99.97
2.17-2.230.23641560.20692818X-RAY DIFFRACTION99.9
2.23-2.290.28921390.24942770X-RAY DIFFRACTION97.78
2.29-2.370.26371510.20412817X-RAY DIFFRACTION100
2.37-2.450.26531390.20432849X-RAY DIFFRACTION100
2.45-2.550.23021580.19912808X-RAY DIFFRACTION100
2.55-2.660.20381390.21452853X-RAY DIFFRACTION99.9
2.66-2.80.2761480.20682813X-RAY DIFFRACTION99.76
2.8-2.980.2571560.19542863X-RAY DIFFRACTION99.97
2.98-3.210.20741580.19492843X-RAY DIFFRACTION99.77
3.21-3.530.20631600.17932867X-RAY DIFFRACTION99.9
3.53-4.040.19331530.16032884X-RAY DIFFRACTION99.74
4.04-5.090.16791600.14132934X-RAY DIFFRACTION100
5.1-58.850.17241650.17093003X-RAY DIFFRACTION98.57
Refinement TLS params.Method: refined / Origin x: 41.5849097239 Å / Origin y: 0.543701253328 Å / Origin z: 19.0996926769 Å
111213212223313233
T0.253349261296 Å20.00667259924529 Å20.0294499746898 Å2-0.270224545356 Å2-0.0187803545251 Å2--0.236827708177 Å2
L0.317971723505 °2-0.481415549101 °20.249114921628 °2-0.702929763386 °2-0.343530959042 °2--0.16871155837 °2
S0.0739674857061 Å °0.0552842561767 Å °-0.0200028844962 Å °-0.135480867154 Å °-0.0534226292081 Å °-0.00407927023827 Å °0.0692946186154 Å °0.0276824659538 Å °-0.0199306934195 Å °
Refinement TLS groupSelection details: all

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