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- PDB-9bg3: Tri-complex of Daraxonrasib (RMC-6236), NRAS Q61K, and CypA -

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Basic information

Entry
Database: PDB / ID: 9bg3
TitleTri-complex of Daraxonrasib (RMC-6236), NRAS Q61K, 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 / SHC1 events in ERBB4 signaling / activation of protein kinase B activity / Binding and entry of HIV virion / 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 / 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 / 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 / Signaling by FGFR2 in disease / positive regulation of endothelial cell proliferation / 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 / 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 / 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 / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / positive regulation of NF-kappaB transcription factor activity / Budding and maturation of HIV virion / Signaling by high-kinase activity BRAF mutants / 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: 1.33 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)77,60411
Polymers74,8534
Non-polymers2,7517
Water17,024945
1
A: GTPase NRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,7845
Polymers37,4272
Non-polymers1,3583
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)38,8206
Polymers37,4272
Non-polymers1,3934
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.880, 84.100, 128.830
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: 19302.918 Da / Num. of mol.: 2 / Mutation: Q61K
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, 952 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: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 945 / 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: 2.38 Å3/Da / Density % sol: 48.4 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 25.5% 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: 1.33→46.06 Å / Num. obs: 164077 / % possible obs: 99.82 % / Redundancy: 7.4 % / Biso Wilson estimate: 18.09 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.09184 / Rpim(I) all: 0.03608 / Rrim(I) all: 0.09882 / Net I/σ(I): 9.2
Reflection shellResolution: 1.33→1.378 Å / Redundancy: 7.6 % / Rmerge(I) obs: 2.449 / Mean I/σ(I) obs: 0.83 / Num. unique obs: 123090 / CC1/2: 0.346 / CC star: 0.717 / Rpim(I) all: 0.9382 / Rrim(I) all: 2.625 / % possible all: 99.5

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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: 1.33→46.06 Å / SU ML: 0.1922 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 22.5539
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1976 8069 4.92 %
Rwork0.1693 155983 -
obs0.1707 164052 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.11 Å2
Refinement stepCycle: LAST / Resolution: 1.33→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5214 0 183 945 6342
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00595650
X-RAY DIFFRACTIONf_angle_d0.8837668
X-RAY DIFFRACTIONf_chiral_restr0.0801821
X-RAY DIFFRACTIONf_plane_restr0.007992
X-RAY DIFFRACTIONf_dihedral_angle_d13.30872175
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.33-1.350.38232940.34915106X-RAY DIFFRACTION99.25
1.35-1.360.39892690.33035144X-RAY DIFFRACTION99.89
1.36-1.380.35352650.31735121X-RAY DIFFRACTION99.37
1.38-1.390.3532590.29565174X-RAY DIFFRACTION99.98
1.39-1.410.34532710.27885096X-RAY DIFFRACTION99.52
1.41-1.430.33412880.27065177X-RAY DIFFRACTION99.65
1.43-1.450.29172540.25245128X-RAY DIFFRACTION99.87
1.45-1.470.29962850.2455133X-RAY DIFFRACTION99.74
1.47-1.50.27772890.2255140X-RAY DIFFRACTION99.8
1.5-1.520.2662470.20775177X-RAY DIFFRACTION100
1.52-1.550.2522550.19625176X-RAY DIFFRACTION99.83
1.55-1.580.21422670.19075129X-RAY DIFFRACTION99.89
1.58-1.610.23262610.18045215X-RAY DIFFRACTION99.91
1.61-1.640.22412800.17685161X-RAY DIFFRACTION99.96
1.64-1.680.21912750.17055171X-RAY DIFFRACTION99.96
1.68-1.710.23882490.16575173X-RAY DIFFRACTION100
1.71-1.760.22112890.16645175X-RAY DIFFRACTION99.96
1.76-1.810.19782450.15825208X-RAY DIFFRACTION99.93
1.81-1.860.21982680.15525205X-RAY DIFFRACTION99.96
1.86-1.920.18652780.15915171X-RAY DIFFRACTION99.82
1.92-1.990.18212390.15355227X-RAY DIFFRACTION99.96
1.99-2.070.18272690.1545235X-RAY DIFFRACTION99.95
2.07-2.160.22022600.15915200X-RAY DIFFRACTION100
2.16-2.270.20872240.16245293X-RAY DIFFRACTION99.84
2.27-2.420.2152600.1635228X-RAY DIFFRACTION100
2.42-2.60.20142890.16725221X-RAY DIFFRACTION99.73
2.6-2.870.20022940.17685253X-RAY DIFFRACTION99.98
2.87-3.280.19342830.16595279X-RAY DIFFRACTION99.62
3.28-4.130.14812710.14475346X-RAY DIFFRACTION99.95
4.13-46.060.15042920.15195521X-RAY DIFFRACTION99.5

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