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- PDB-9ctb: Tri-complex of zoldonrasib (RMC-9805), KRAS G12D, and CypA -

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Basic information

Entry
Database: PDB / ID: 9ctb
TitleTri-complex of zoldonrasib (RMC-9805), KRAS G12D, and CypA
Components
  • Isoform 2B of GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / KRAS / CypA / G12D / GTPase / tri-complex / inhibitor-complex / HYDROLASE / HYDROLASE-HYDROLASE 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 / 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 / lipid droplet organization / negative regulation of viral life cycle / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / protein peptidyl-prolyl isomerization / forebrain astrocyte development / Basigin interactions / negative regulation of epithelial cell differentiation / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / Early Phase of HIV Life Cycle / Integration of provirus / 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 / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / viral release from host cell / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / 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 / activation of protein kinase B activity / Binding and entry of HIV virion / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / positive regulation of viral genome replication / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / 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 oxidative stress-induced intrinsic apoptotic signaling pathway / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / negative regulation of protein kinase activity / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / GRB2 events in EGFR signaling / neutrophil chemotaxis / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / homeostasis of number of cells within a tissue / 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 / 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 / small monomeric GTPase / peptidyl-prolyl cis-trans 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 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: 1.29 Å
AuthorsZhang, D. / Bar Ziv, T. / Tomlinson, A.C.A. / Saldajeno-Concar, M. / Yano, J.K. / Knox, J.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Science / Year: 2025
Title: A neomorphic protein interface catalyzes covalent inhibition of RAS
Authors: Wildes, D.
History
DepositionJul 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)78,58612
Polymers75,0814
Non-polymers3,5058
Water14,610811
1
D: Peptidyl-prolyl cis-trans isomerase A
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2936
Polymers37,5402
Non-polymers1,7524
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Peptidyl-prolyl cis-trans isomerase A
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2936
Polymers37,5402
Non-polymers1,7524
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.510, 101.840, 66.760
Angle α, β, γ (deg.)90.000, 90.750, 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 DCBA

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


Mass: 19416.873 Da / Num. of mol.: 2 / Mutation: G12D
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

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Non-polymers , 5 types, 819 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-A1AZZ / (2R)-2-cyclopentyl-2-{(5S)-7-[(2R)-3-cyclopropyl-2-(methylamino)propanoyl]-2,7-diazaspiro[4.4]nonan-2-yl}-N-[(2S,6R,8S,10R,14S,21M)-21-{5-(4-cyclopropylpiperazin-1-yl)-2-[(1R)-1-methoxyethyl]pyridin-3-yl}-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-5,16-dioxa-2,10,22,28-tetraazapentacyclo[18.5.2.1~2,6~.1~10,14~.0~23,27~]nonacosa-1(25),20,23,26-tetraen-8-yl]acetamide (non-preferred name)


Mass: 1170.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C63H90F3N11O7 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 811 / 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: 2.16 Å3/Da / Density % sol: 42.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 0.1 M MES 5.5, 20% PEG3350, 0.1 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.95302 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jan 12, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95302 Å / Relative weight: 1
ReflectionResolution: 1.29→35.99 Å / Num. obs: 154502 / % possible obs: 97.13 % / Redundancy: 3.9 % / Biso Wilson estimate: 17.25 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.0668 / Net I/σ(I): 8.22
Reflection shellResolution: 1.29→1.336 Å / Num. unique obs: 15130 / CC1/2: 0.33

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.29→35.99 Å / SU ML: 0.1664 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.0959
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1936 7526 4.87 %
Rwork0.1573 146949 -
obs0.1591 154475 97.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.3 Å2
Refinement stepCycle: LAST / Resolution: 1.29→35.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5251 0 236 811 6298
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00495748
X-RAY DIFFRACTIONf_angle_d0.98747801
X-RAY DIFFRACTIONf_chiral_restr0.0816836
X-RAY DIFFRACTIONf_plane_restr0.0078994
X-RAY DIFFRACTIONf_dihedral_angle_d14.27272218
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.29-1.30.33962540.30854765X-RAY DIFFRACTION95.29
1.3-1.320.31132490.31254787X-RAY DIFFRACTION95.25
1.32-1.340.35222380.34832X-RAY DIFFRACTION95.46
1.34-1.350.31442700.28044795X-RAY DIFFRACTION95.82
1.35-1.370.30352370.26844791X-RAY DIFFRACTION95.59
1.37-1.390.29152370.25654856X-RAY DIFFRACTION96.04
1.39-1.410.2922370.24434809X-RAY DIFFRACTION95.86
1.41-1.430.30672530.23954822X-RAY DIFFRACTION96.1
1.43-1.450.25052590.21664851X-RAY DIFFRACTION96.29
1.45-1.480.25732440.20544867X-RAY DIFFRACTION96.47
1.48-1.50.24242520.19254842X-RAY DIFFRACTION96.55
1.5-1.530.24292160.18354920X-RAY DIFFRACTION96.81
1.53-1.560.19872480.17644863X-RAY DIFFRACTION96.91
1.56-1.590.25862570.16754889X-RAY DIFFRACTION96.93
1.59-1.630.21622490.16544879X-RAY DIFFRACTION96.7
1.63-1.660.20522450.15424884X-RAY DIFFRACTION97.2
1.66-1.70.21862570.15414908X-RAY DIFFRACTION97.69
1.7-1.750.21882180.15594948X-RAY DIFFRACTION97.67
1.75-1.80.21332390.15484940X-RAY DIFFRACTION97.7
1.8-1.860.20172700.15354932X-RAY DIFFRACTION97.97
1.86-1.930.19072720.14714919X-RAY DIFFRACTION98.13
1.93-20.19592560.14334971X-RAY DIFFRACTION98.33
2-2.10.17522820.14324913X-RAY DIFFRACTION98.09
2.1-2.210.19212280.14675003X-RAY DIFFRACTION98.31
2.21-2.340.20022420.14434979X-RAY DIFFRACTION98.45
2.34-2.520.19942870.15084940X-RAY DIFFRACTION98.27
2.52-2.780.2012400.16395002X-RAY DIFFRACTION98.42
2.78-3.180.19742740.15834949X-RAY DIFFRACTION97.77
3.18-4.010.1562540.13375023X-RAY DIFFRACTION99.27
4.01-35.990.14752620.13665070X-RAY DIFFRACTION98.59

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