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- PDB-9bg8: Tri-complex of Daraxonrasib (RMC-6236), NRAS Q61R, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bg8
TitleTri-complex of Daraxonrasib (RMC-6236), NRAS Q61R, and CypA
Components
  • GTPase NRas
  • 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 / protein peptidyl-prolyl isomerization / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / Integration of provirus / negative regulation of protein phosphorylation / 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 / tertiary granule membrane / RAS signaling downstream of NF1 loss-of-function variants / Calcineurin activates NFAT / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / activation of protein kinase B activity / SHC1 events in ERBB4 signaling / Binding and entry of HIV virion / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / positive regulation of viral genome replication / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / SHC-mediated cascade:FGFR2 / negative regulation of protein kinase activity / 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 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / 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 / Tie2 Signaling / positive regulation of endothelial cell proliferation / 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 / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / positive regulation of protein secretion / FCERI mediated MAPK activation / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / Assembly Of The HIV Virion / Signaling by ERBB2 TMD/JMD mutants / RAF activation / positive regulation of NF-kappaB transcription factor activity / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Budding and maturation of HIV virion / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / platelet aggregation / integrin binding / positive regulation of protein phosphorylation / neuron differentiation
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. / Rho (Ras homology) subfamily of Ras-like 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. / 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 NRas / 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. / 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 NRas
B: GTPase NRas
C: Peptidyl-prolyl cis-trans isomerase A
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,04312
Polymers74,9094
Non-polymers3,1348
Water17,511972
1
A: GTPase NRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0216
Polymers37,4552
Non-polymers1,5674
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase NRas
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0216
Polymers37,4552
Non-polymers1,5674
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.010, 84.100, 127.420
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 NRas / Transforming protein N-Ras


Mass: 19330.934 Da / Num. of mol.: 2 / Mutation: Q61R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01111, 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 , 5 types, 980 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-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 972 / 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: 2.36 Å3/Da / Density % sol: 47.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% PEG3350, 0.1 M Bis-Tris, pH 5.5, 150 mM sodium chloride

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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: Feb 2, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.2→45.84 Å / Num. obs: 220757 / % possible obs: 99.88 % / Redundancy: 7.4 % / Biso Wilson estimate: 15.25 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.07218 / Rpim(I) all: 0.02848 / Rrim(I) all: 0.0777 / Net I/σ(I): 11.4
Reflection shellResolution: 1.2→1.243 Å / Redundancy: 6.9 % / Rmerge(I) obs: 2.119 / Mean I/σ(I) obs: 1.05 / Num. unique obs: 21857 / CC1/2: 0.399 / CC star: 0.755 / Rpim(I) all: 0.8667 / Rrim(I) all: 2.293 / % possible all: 99.81

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→40.25 Å / SU ML: 0.1312 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.3397
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1858 11100 5.03 %
Rwork0.1523 209636 -
obs0.154 220736 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.53 Å2
Refinement stepCycle: LAST / Resolution: 1.2→40.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5211 0 210 972 6393
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00525655
X-RAY DIFFRACTIONf_angle_d0.86667662
X-RAY DIFFRACTIONf_chiral_restr0.0814812
X-RAY DIFFRACTIONf_plane_restr0.0072990
X-RAY DIFFRACTIONf_dihedral_angle_d12.72942184
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.210.31033940.29046912X-RAY DIFFRACTION99.81
1.21-1.230.29253860.28696818X-RAY DIFFRACTION99.81
1.23-1.240.26963840.26236959X-RAY DIFFRACTION99.84
1.24-1.260.28013760.24716897X-RAY DIFFRACTION99.88
1.26-1.280.29623580.24376950X-RAY DIFFRACTION99.95
1.28-1.290.28253650.24456964X-RAY DIFFRACTION99.85
1.29-1.310.27233710.25666871X-RAY DIFFRACTION99.79
1.31-1.330.22793650.20896939X-RAY DIFFRACTION99.8
1.33-1.350.24153740.19836956X-RAY DIFFRACTION99.95
1.35-1.370.21853460.18816968X-RAY DIFFRACTION99.9
1.37-1.40.23793300.17836930X-RAY DIFFRACTION99.78
1.4-1.420.20583730.16876960X-RAY DIFFRACTION99.93
1.42-1.450.22683620.16276935X-RAY DIFFRACTION99.92
1.45-1.480.2043920.15516933X-RAY DIFFRACTION99.92
1.48-1.510.19633650.1476943X-RAY DIFFRACTION99.99
1.51-1.550.17854040.12786948X-RAY DIFFRACTION99.93
1.55-1.590.18373610.13036974X-RAY DIFFRACTION99.97
1.59-1.630.17573770.12846939X-RAY DIFFRACTION99.97
1.63-1.680.16853900.12196985X-RAY DIFFRACTION99.96
1.68-1.730.17613350.12477012X-RAY DIFFRACTION99.96
1.73-1.790.17373570.12677018X-RAY DIFFRACTION99.97
1.79-1.860.16873540.1317004X-RAY DIFFRACTION99.93
1.86-1.950.18233560.1476991X-RAY DIFFRACTION99.7
1.95-2.050.18174000.1347006X-RAY DIFFRACTION99.96
2.05-2.180.15663330.13727066X-RAY DIFFRACTION99.97
2.18-2.350.19043810.14617043X-RAY DIFFRACTION99.78
2.35-2.590.19343930.14747015X-RAY DIFFRACTION99.92
2.59-2.960.18423560.16017143X-RAY DIFFRACTION99.97
2.96-3.730.17323710.15077164X-RAY DIFFRACTION99.99
3.73-40.250.16253910.14247393X-RAY DIFFRACTION99.43

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