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- PDB-9bfw: Tri-complex of Compound-4, KRAS G12C, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bfw
TitleTri-complex of Compound-4, KRAS G12C, and CypA
Components
  • GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN/INHIBITOR / inhibitor / complex / small GTPase / cancer / tricomplex / 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: 1.2 Å
AuthorsTomlinson, A.C.A. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers.
Authors: Cregg, J. / Pota, K. / Tomlinson, A.C.A. / Yano, J. / Marquez, A. / Liu, Y. / Schulze, C.J. / Seamon, K.J. / Holderfield, M. / Wei, X. / Zhuang, Y. / Yang, Y.C. / Jiang, J. / Huang, Y. / ...Authors: Cregg, J. / Pota, K. / Tomlinson, A.C.A. / Yano, J. / Marquez, A. / Liu, Y. / Schulze, C.J. / Seamon, K.J. / Holderfield, M. / Wei, X. / Zhuang, Y. / Yang, Y.C. / Jiang, J. / Huang, Y. / Zhao, R. / Ling, Y. / Wang, Z. / Flagella, M. / Wang, Z. / Singh, M. / Knox, J.E. / Nichols, R. / Wildes, D. / Smith, J.A.M. / Koltun, E.S. / Gill, A.L.
History
DepositionApr 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 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
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9866
Polymers37,4902
Non-polymers1,4964
Water9,890549
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.210, 58.080, 75.950
Angle α, β, γ (deg.)90.000, 97.950, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 2 types, 2 molecules AD

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


Mass: 19382.811 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, small monomeric GTPase
#2: Protein Peptidyl-prolyl cis-trans isomerase A / PPIase A / Cyclophilin A / Cyclosporin A-binding protein / Rotamase A


Mass: 18107.516 Da / Num. of mol.: 1
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 , 5 types, 553 molecules

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


Mass: 522.196 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical ChemComp-A1AOM / 1-acetyl-N-[(2S)-1-{[(1M,8S,10R,14S,20S)-22-cyano-4-hydroxy-18,18-dimethyl-9,15-dioxo-16-oxa-10,20,28-triazapentacyclo[18.5.2.1~2,6~.1~10,14~.0~23,27~]nonacosa-1(25),2(29),3,5,21,23,26-heptaen-8-yl]amino}-3-methyl-1-oxobutan-2-yl]-N-methylazetidine-3-carboxamide (non-preferred name)


Mass: 739.860 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H49N7O7 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 549 / 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: 2.17 Å3/Da / Density % sol: 43.27 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 25% PEG 3350, 0.1M Bis Tris, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.953 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 5, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.953 Å / Relative weight: 1
ReflectionResolution: 1.2→35.07 Å / Num. obs: 99659 / % possible obs: 99.61 % / Redundancy: 3.7 % / Biso Wilson estimate: 10.26 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.04415 / Rpim(I) all: 0.02607 / Rrim(I) all: 0.05144 / Net I/σ(I): 15.35
Reflection shellResolution: 1.2→1.243 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.1992 / Mean I/σ(I) obs: 4.98 / Num. unique obs: 9775 / CC1/2: 0.947 / CC star: 0.986 / Rpim(I) all: 0.1258 / Rrim(I) all: 0.2368 / % possible all: 98.16

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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: 1.2→35.07 Å / SU ML: 0.0915 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 12.9076
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1475 4936 4.95 %
Rwork0.121 94710 -
obs0.1223 99646 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 16.18 Å2
Refinement stepCycle: LAST / Resolution: 1.2→35.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2614 0 101 549 3264
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00512926
X-RAY DIFFRACTIONf_angle_d1.17093973
X-RAY DIFFRACTIONf_chiral_restr0.0829420
X-RAY DIFFRACTIONf_plane_restr0.0067519
X-RAY DIFFRACTIONf_dihedral_angle_d13.9061110
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.210.18841480.18113008X-RAY DIFFRACTION95.2
1.21-1.230.19481540.13473132X-RAY DIFFRACTION99.61
1.23-1.240.17061620.12893165X-RAY DIFFRACTION99.67
1.24-1.260.16491600.12133165X-RAY DIFFRACTION99.76
1.26-1.280.14961860.11433120X-RAY DIFFRACTION99.82
1.28-1.290.14751690.11633146X-RAY DIFFRACTION99.88
1.29-1.310.14851620.11173173X-RAY DIFFRACTION99.88
1.31-1.330.15611520.113190X-RAY DIFFRACTION99.82
1.33-1.350.14461640.10823128X-RAY DIFFRACTION99.76
1.35-1.370.15011520.10813145X-RAY DIFFRACTION99.88
1.37-1.40.14011590.10713136X-RAY DIFFRACTION99.97
1.4-1.420.14631660.10773143X-RAY DIFFRACTION99.61
1.42-1.450.13931760.11213180X-RAY DIFFRACTION99.73
1.45-1.480.12811770.10923125X-RAY DIFFRACTION99.85
1.48-1.510.13191540.10533136X-RAY DIFFRACTION99.64
1.51-1.550.13911510.1043200X-RAY DIFFRACTION99.64
1.55-1.590.13881770.10353102X-RAY DIFFRACTION99.82
1.59-1.630.13771690.10243183X-RAY DIFFRACTION99.79
1.63-1.680.13651670.1053152X-RAY DIFFRACTION99.88
1.68-1.730.14841520.11283176X-RAY DIFFRACTION99.94
1.73-1.790.1441710.11793161X-RAY DIFFRACTION99.88
1.79-1.860.1581530.11953230X-RAY DIFFRACTION99.88
1.86-1.950.15941650.11623116X-RAY DIFFRACTION99.79
1.95-2.050.15231760.11553164X-RAY DIFFRACTION99.79
2.05-2.180.13961690.11733163X-RAY DIFFRACTION99.82
2.18-2.350.14811680.12423189X-RAY DIFFRACTION99.67
2.35-2.590.14691600.13323129X-RAY DIFFRACTION99.13
2.59-2.960.16361680.13673200X-RAY DIFFRACTION99.94
2.96-3.730.14581700.12483200X-RAY DIFFRACTION99.67
3.73-35.070.13851790.12993253X-RAY DIFFRACTION99.59

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