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- PDB-9bgb: Tri-complex of Daraxonrasib (RMC-6236), KRAS Q61H, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bgb
TitleTri-complex of Daraxonrasib (RMC-6236), KRAS Q61H, 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
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / negative regulation of viral life cycle / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / virion binding / negative regulation of stress-activated MAPK cascade ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / negative regulation of viral life cycle / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / virion binding / negative regulation of stress-activated MAPK cascade / endothelial cell activation / Basigin interactions / response to mineralocorticoid / GMP binding / forebrain astrocyte development / protein peptidyl-prolyl isomerization / LRR domain binding / cyclosporin A binding / regulation of synaptic transmission, GABAergic / Minus-strand DNA synthesis / Plus-strand DNA synthesis / negative regulation of epithelial cell differentiation / Uncoating of the HIV Virion / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / Early Phase of HIV Life Cycle / type I pneumocyte differentiation / Integration of provirus / Rac protein signal transduction / negative regulation of protein phosphorylation / APOBEC3G mediated resistance to HIV-1 infection / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / viral release from host cell / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Calcineurin activates NFAT / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / activation of protein kinase B activity / Binding and entry of HIV virion / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / positive regulation of viral genome replication / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / SHC-mediated cascade:FGFR2 / 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:FGFR4 / negative regulation of protein kinase activity / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / neutrophil chemotaxis / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation
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 domain 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 domain 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: 1.68 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

Downloads & links

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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)77,70010
Polymers74,9854
Non-polymers2,7156
Water7,278404
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8505
Polymers37,4922
Non-polymers1,3583
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)38,8505
Polymers37,4922
Non-polymers1,3583
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.150, 80.600, 127.270
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: 19368.855 Da / Num. of mol.: 2 / Mutation: Q61H
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, 410 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-A1AHB / (1R,2S)-N-[(1P,7S,9S,13R,20M)-21-ethyl-20-{2-[(1R)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)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


Mass: 811.047 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H58N8O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 404 / 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: 2.26 Å3/Da / Density % sol: 45.48 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 29% PEG4000, 0.1 M Tris, pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 19, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.68→39.64 Å / Num. obs: 76785 / % possible obs: 99.62 % / Redundancy: 7.6 % / Biso Wilson estimate: 26.14 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1125 / Rpim(I) all: 0.04336 / Rrim(I) all: 0.1208 / Net I/σ(I): 10.46
Reflection shellResolution: 1.68→1.74 Å / Redundancy: 8 % / Rmerge(I) obs: 2.831 / Mean I/σ(I) obs: 0.81 / Num. unique obs: 7556 / CC1/2: 0.33 / CC star: 0.705 / Rpim(I) all: 1.057 / Rrim(I) all: 3.025 / % possible all: 99.39

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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: 1.68→39.64 Å / SU ML: 0.2724 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.2099
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2304 3882 5.06 %
Rwork0.1982 72892 -
obs0.1998 76774 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.45 Å2
Refinement stepCycle: LAST / Resolution: 1.68→39.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5185 0 182 404 5771
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075513
X-RAY DIFFRACTIONf_angle_d0.86957460
X-RAY DIFFRACTIONf_chiral_restr0.0565797
X-RAY DIFFRACTIONf_plane_restr0.0072959
X-RAY DIFFRACTIONf_dihedral_angle_d13.57232090
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.68-1.70.44161190.41042596X-RAY DIFFRACTION99.89
1.7-1.720.42071490.38762527X-RAY DIFFRACTION98.49
1.72-1.740.39391420.35372548X-RAY DIFFRACTION99.89
1.74-1.770.37651470.35032560X-RAY DIFFRACTION98.69
1.77-1.790.34461470.31632576X-RAY DIFFRACTION99.89
1.79-1.820.30861170.29352549X-RAY DIFFRACTION98.81
1.82-1.850.32351370.27352596X-RAY DIFFRACTION99.96
1.85-1.880.30431350.26552567X-RAY DIFFRACTION99.08
1.88-1.910.26231340.24192588X-RAY DIFFRACTION99.71
1.91-1.950.29071250.23442537X-RAY DIFFRACTION99.4
1.95-1.980.26761520.22952581X-RAY DIFFRACTION99.38
1.98-2.020.24941370.22442598X-RAY DIFFRACTION99.89
2.02-2.070.25641560.20932560X-RAY DIFFRACTION99.52
2.07-2.120.24921300.20012613X-RAY DIFFRACTION99.6
2.12-2.170.2691390.19042572X-RAY DIFFRACTION99.74
2.17-2.230.25951460.18692579X-RAY DIFFRACTION99.71
2.23-2.290.24891560.18382563X-RAY DIFFRACTION99.63
2.29-2.370.23151330.18222611X-RAY DIFFRACTION99.82
2.37-2.450.20121360.1832610X-RAY DIFFRACTION99.82
2.45-2.550.23551290.19472618X-RAY DIFFRACTION99.89
2.55-2.670.27081450.20872598X-RAY DIFFRACTION100
2.67-2.810.25671280.21212651X-RAY DIFFRACTION99.89
2.81-2.980.24031420.20212636X-RAY DIFFRACTION99.93
2.98-3.210.23381290.20072632X-RAY DIFFRACTION99.6
3.21-3.540.19921370.18142636X-RAY DIFFRACTION99.93
3.54-4.050.18551340.16552684X-RAY DIFFRACTION100
4.05-5.10.16581480.15672691X-RAY DIFFRACTION99.82
5.1-39.640.21471530.18382815X-RAY DIFFRACTION99.73

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