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- PDB-9bg7: Tri-complex of Compound-6, KRAS G12V, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bg7
TitleTri-complex of Compound-6, KRAS G12V, and CypA
Components
  • Isoform 2B of 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: 1.6 Å
AuthorsTomlinson, A.C.A. / Saldajeno-Concar, M. / 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)77,81210
Polymers75,0054
Non-polymers2,8076
Water15,079837
1
A: Isoform 2B of GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9065
Polymers37,5022
Non-polymers1,4043
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9065
Polymers37,5022
Non-polymers1,4043
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.683, 101.920, 66.731
Angle α, β, γ (deg.)90.000, 90.810, 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, 4 molecules ABDC

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


Mass: 19378.799 Da / Num. of mol.: 2 / Mutation: G12V
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, 843 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-A1AOI / N-[(2R)-1-{[(1P,7S,9S,13R,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]amino}-3-methyl-1-oxobutan-2-yl]-3-methoxy-N-methylazetidine-1-carboxamide (non-preferred name)


Mass: 857.072 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C45H60N8O7S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 837 / 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: 2.18 Å3/Da / Density % sol: 43.46 %
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: SSRL / Beamline: BL14-1 / Wavelength: 1.19499 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.19499 Å / Relative weight: 1
ReflectionResolution: 1.6→39.06 Å / Num. obs: 76408 / % possible obs: 91.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 17.02 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.045 / Net I/σ(I): 10.8
Reflection shellResolution: 1.6→1.63 Å / Rmerge(I) obs: 0.683 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2034 / CC1/2: 0.47 / Rpim(I) all: 0.615 / % possible all: 49.3

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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: 1.6→39.06 Å / SU ML: 0.1826 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.0549
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2033 3743 4.91 %
Rwork0.1652 72454 -
obs0.1671 76197 90.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.21 Å2
Refinement stepCycle: LAST / Resolution: 1.6→39.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5234 0 188 837 6259
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00585605
X-RAY DIFFRACTIONf_angle_d0.91267589
X-RAY DIFFRACTIONf_chiral_restr0.0529813
X-RAY DIFFRACTIONf_plane_restr0.0083983
X-RAY DIFFRACTIONf_dihedral_angle_d13.20822107
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.620.2576780.24721394X-RAY DIFFRACTION48.15
1.62-1.640.284850.231635X-RAY DIFFRACTION55.22
1.64-1.660.3012920.22831799X-RAY DIFFRACTION61.64
1.66-1.690.27481060.2212024X-RAY DIFFRACTION68.69
1.69-1.710.27191060.20792248X-RAY DIFFRACTION75.5
1.71-1.740.26781380.20452367X-RAY DIFFRACTION81.81
1.74-1.770.22181190.19882737X-RAY DIFFRACTION91.07
1.77-1.80.22361510.19642873X-RAY DIFFRACTION98.41
1.8-1.830.28141510.21172961X-RAY DIFFRACTION99.27
1.83-1.870.24411600.20492874X-RAY DIFFRACTION98.96
1.87-1.90.25891390.19882954X-RAY DIFFRACTION98.75
1.9-1.950.25691500.20052801X-RAY DIFFRACTION96.88
1.95-1.990.20591530.1732925X-RAY DIFFRACTION98.4
1.99-2.040.22661520.16782891X-RAY DIFFRACTION98.61
2.04-2.10.22751290.18592870X-RAY DIFFRACTION96.56
2.1-2.160.19871400.16682900X-RAY DIFFRACTION97.62
2.16-2.230.20621420.16692879X-RAY DIFFRACTION98.08
2.23-2.310.22151640.17422926X-RAY DIFFRACTION98.82
2.31-2.40.17561620.16442942X-RAY DIFFRACTION99.87
2.4-2.510.25061590.16752929X-RAY DIFFRACTION99.48
2.51-2.640.22981400.17432932X-RAY DIFFRACTION99
2.64-2.810.23641390.17282939X-RAY DIFFRACTION98.62
2.81-3.020.18891740.17082848X-RAY DIFFRACTION97.42
3.02-3.330.20031540.15412905X-RAY DIFFRACTION98.52
3.33-3.810.19611490.13622957X-RAY DIFFRACTION99.55
3.81-4.80.15351570.12642989X-RAY DIFFRACTION99.62
4.8-39.060.13151540.14552955X-RAY DIFFRACTION98.11
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.9326879616460.5050926336750.4992023419081.735993076860.1019057401331.762689577840.078031998586-0.0345112561235-0.09574056851040.1188475525750.0629972502304-0.1411415877660.08711314115790.045529007634-0.1145739345960.1056342828610.0139716642351-0.02643129216560.109179206672-0.009315242588610.135724468747-27.6585590571-36.602738069628.9230307108
21.74831833440.248108237189-0.5412134590011.401837065610.1357471166861.934660508320.0248396134441-0.01125851879840.07460101712680.083346164733-0.00839086896187-0.01614790142860.02117031525070.0385498234655-0.01482396393270.0870351210014-0.00730134806177-0.009331799373510.07967171430130.009606827989860.0934713623133-5.50117104565-12.980601326234.8607383
31.26032484903-0.28945308398-0.6586939734311.09947128869-0.08307152442881.549524090920.08531354242230.1246851919180.0637816082096-0.1724073656030.010542235525-0.0512804054189-0.1844750170390.0178643887758-0.08190738078120.152712970671-0.01781002422840.01604806477890.123883214523-0.01244057057560.094018952028-26.9540773503-18.88188923391.15338653496
41.39827060477-0.01121633134020.07230558417251.529778129450.6382732891912.16328446337-0.0384650501288-0.100892262359-0.03566139752830.0414377113730.0482654276477-0.01548428522270.01413029021350.105765198442-0.006543826151060.09085848911970.00670329929641-0.003517022443820.1021858099050.001118138638270.0810001979456-4.82880074629-42.339893102-4.76812052234
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 0 through 167)AA0 - 1671 - 168
22(chain 'D' and resid 2 through 201)DD - E2 - 2011
33(chain 'B' and resid 1 through 167)BF1 - 1672 - 168
44(chain 'C' and resid 0 through 201)CI - J0 - 2011

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