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- PDB-9e3s: Tricomplex of RMC-9945, KRAS G12N, and CypA -

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Basic information

Entry
Database: PDB / ID: 9e3s
TitleTricomplex of RMC-9945, KRAS G12N, and CypA
Components
  • Isoform 2B of GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN / KRAS / CypA / G12N / GTPase / tri-complex / 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: 1.08 Å
AuthorsZhang, D. / Bar Ziv, T. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Science / Year: 2025
Title: A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors.
Authors: Weller, C. / Burnett, G.L. / Jiang, L. / Chakraborty, S. / Zhang, D. / Vita, N.A. / Dilly, J. / Kim, E. / Maldonato, B. / Seamon, K. / Eilerts, D.F. / Milin, A. / Marquez, A. / Spradlin, J. ...Authors: Weller, C. / Burnett, G.L. / Jiang, L. / Chakraborty, S. / Zhang, D. / Vita, N.A. / Dilly, J. / Kim, E. / Maldonato, B. / Seamon, K. / Eilerts, D.F. / Milin, A. / Marquez, A. / Spradlin, J. / Helland, C. / Gould, A. / Ziv, T.B. / Dinh, P. / Steele, S.L. / Wang, Z. / Mu, Y. / Chugh, S. / Feng, H. / Hennessey, C. / Wang, J. / Roth, J. / Rees, M. / Ronan, M. / Wolpin, B.M. / Hahn, W.C. / Holderfield, M. / Wang, Z. / Koltun, E.S. / Singh, M. / Gill, A.L. / Smith, J.A.M. / Aguirre, A.J. / Jiang, J. / Knox, J.E. / Wildes, D.
History
DepositionOct 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 6, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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
B: Isoform 2B of 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)78,61613
Polymers75,0794
Non-polymers3,5379
Water17,763986
1
A: Isoform 2B of GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3547
Polymers37,5392
Non-polymers1,8145
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)39,2626
Polymers37,5392
Non-polymers1,7224
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.920, 101.500, 66.800
Angle α, β, γ (deg.)90.000, 90.640, 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 ABCD

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


Mass: 19415.889 Da / Num. of mol.: 2
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 , 6 types, 995 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-A1BEA / (2R)-2-{(5S)-7-[(2R,3R)-3-cyclopropyl-1-methylaziridine-2-carbonyl]-2,7-diazaspiro[4.4]nonan-2-yl}-N-[(1P,7S,9S,13S,20M)-20-{5-(4-cyclopropylpiperazin-1-yl)-2-[(1R)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-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]-3-methylbutanamide (non-preferred name)


Mass: 1140.408 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C60H80F3N11O6S / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 986 / 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: 2.16 Å3/Da / Density % sol: 43.15 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M MES 6 pH, 0.1-0.2 M NaCl, 21-26 %w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00004 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 23, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 1.08→43.33 Å / Num. obs: 255378 / % possible obs: 93.81 % / Redundancy: 3.3 % / Biso Wilson estimate: 11.07 Å2 / CC1/2: 0.998 / Net I/σ(I): 8.23
Reflection shellResolution: 1.08→1.19 Å / Rmerge(I) obs: 0.9804 / Num. unique obs: 19081 / CC1/2: 0.326

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.08→43.33 Å / SU ML: 0.1159 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.5382
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1778 12984 5.08 %
Rwork0.1511 242375 -
obs0.1525 255359 93.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.93 Å2
Refinement stepCycle: LAST / Resolution: 1.08→43.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5242 0 236 986 6464
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00645945
X-RAY DIFFRACTIONf_angle_d1.06698104
X-RAY DIFFRACTIONf_chiral_restr0.0912863
X-RAY DIFFRACTIONf_plane_restr0.01141050
X-RAY DIFFRACTIONf_dihedral_angle_d11.5132965
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.08-1.090.34222860.33065326X-RAY DIFFRACTION62.27
1.09-1.110.34433070.31126106X-RAY DIFFRACTION70.77
1.11-1.120.28833380.29366719X-RAY DIFFRACTION77.97
1.12-1.130.29234070.27347280X-RAY DIFFRACTION84.76
1.13-1.150.2694450.2497774X-RAY DIFFRACTION90.91
1.15-1.160.26894710.23168099X-RAY DIFFRACTION94.69
1.16-1.180.24244290.22078204X-RAY DIFFRACTION95.32
1.18-1.20.24474110.21488307X-RAY DIFFRACTION95.56
1.2-1.220.23594350.21288199X-RAY DIFFRACTION96.11
1.22-1.240.24424450.20018284X-RAY DIFFRACTION95.94
1.24-1.260.21624190.19698169X-RAY DIFFRACTION94.95
1.26-1.280.22284210.1888313X-RAY DIFFRACTION96.95
1.28-1.310.20695040.18158336X-RAY DIFFRACTION97.19
1.31-1.330.2073950.17438458X-RAY DIFFRACTION97.51
1.33-1.360.21854400.16618360X-RAY DIFFRACTION97.42
1.36-1.390.18264270.15368352X-RAY DIFFRACTION97.06
1.39-1.430.17494400.1568305X-RAY DIFFRACTION96.57
1.43-1.470.18753960.14228337X-RAY DIFFRACTION96.04
1.47-1.510.16194330.13468453X-RAY DIFFRACTION97.94
1.51-1.560.17214390.13058476X-RAY DIFFRACTION98.11
1.56-1.610.15584940.12338405X-RAY DIFFRACTION98.42
1.61-1.680.15335560.12598397X-RAY DIFFRACTION98.6
1.68-1.750.16534660.13738342X-RAY DIFFRACTION97.04
1.75-1.850.16334530.13818394X-RAY DIFFRACTION97.33
1.85-1.960.16634580.13428529X-RAY DIFFRACTION98.98
1.96-2.110.15815070.12968502X-RAY DIFFRACTION98.82
2.11-2.330.15194710.13388444X-RAY DIFFRACTION98.29
2.33-2.660.17884150.14488384X-RAY DIFFRACTION96.23
2.66-3.360.174160.14468587X-RAY DIFFRACTION98.76
3.36-43.330.15324600.13138534X-RAY DIFFRACTION97.52

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