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- PDB-9ax6: Tricomplex of RMC-6236, KRAS G12D, and CypA -

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Basic information

Entry
Database: PDB / ID: 9ax6
TitleTricomplex of RMC-6236, KRAS G12D, and CypA
Components
  • GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsSIGNALING PROTEIN/INHIBITOR / inhibitor / complex / small GTPase / cancer / tricomplex / 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 / negative regulation of viral life cycle / lipid droplet organization / 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 / negative regulation of viral life cycle / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / forebrain astrocyte development / Basigin interactions / protein peptidyl-prolyl isomerization / negative regulation of epithelial cell differentiation / cyclosporin A binding / type I pneumocyte differentiation / Minus-strand DNA synthesis / Plus-strand DNA synthesis / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Uncoating of the HIV Virion / Rac protein signal transduction / Early Phase of HIV Life Cycle / Integration of provirus / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of protein phosphorylation / 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 / Binding and entry of HIV virion / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / positive regulation of viral genome replication / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / activation of protein kinase B activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / neutrophil chemotaxis / 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 / Ras activation upon Ca2+ influx through NMDA receptor / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / 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 / peptidyl-prolyl cis-trans isomerase activity / small monomeric GTPase / negative regulation of protein kinase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 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 family 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 family 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: 1.65 Å
AuthorsTomlinson, A.C.A. / Saldajeno-Concar, M. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Discov / Year: 2024
Title: Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.
Authors: Jiang, J. / Jiang, L. / Maldonato, B.J. / Wang, Y. / Holderfield, M. / Aronchik, I. / Winters, I.P. / Salman, Z. / Blaj, C. / Menard, M. / Brodbeck, J. / Chen, Z. / Wei, X. / Rosen, M.J. / ...Authors: Jiang, J. / Jiang, L. / Maldonato, B.J. / Wang, Y. / Holderfield, M. / Aronchik, I. / Winters, I.P. / Salman, Z. / Blaj, C. / Menard, M. / Brodbeck, J. / Chen, Z. / Wei, X. / Rosen, M.J. / Gindin, Y. / Lee, B.J. / Evans, J.W. / Chang, S. / Wang, Z. / Seamon, K.J. / Parsons, D. / Cregg, J. / Marquez, A. / Tomlinson, A.C.A. / Yano, J.K. / Knox, J.E. / Quintana, E. / Aguirre, A.J. / Arbour, K.C. / Reed, A. / Gustafson, W.C. / Gill, A.L. / Koltun, E.S. / Wildes, D. / Smith, J.A.M. / Wang, Z. / Singh, M.
History
DepositionMar 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
D: Peptidyl-prolyl cis-trans isomerase A
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,75210
Polymers75,0374
Non-polymers2,7156
Water10,016556
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8765
Polymers37,5182
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)38,8765
Polymers37,5182
Non-polymers1,3583
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.240, 84.140, 127.800
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 ABDC

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


Mass: 19394.758 Da / Num. of mol.: 2 / Mutation: G12D, C51S, C80L, C118S
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, 562 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.: 556 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.37 Å3/Da / Density % sol: 48.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 0.1 M Tris, pH 8.0, 25% PEG4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.65→52.05 Å / Num. obs: 85162 / % possible obs: 98.37 % / Redundancy: 6.7 % / Biso Wilson estimate: 27.6 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.028 / Rrim(I) all: 0.072 / Net I/σ(I): 14.21
Reflection shellResolution: 1.65→1.709 Å / Rmerge(I) obs: 2.286 / Mean I/σ(I) obs: 0.87 / Num. unique obs: 8346 / CC1/2: 0.469 / Rpim(I) all: 0.928 / Rrim(I) all: 2.47

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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: 1.65→52.05 Å / SU ML: 0.2907 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.9794
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2265 4236 4.98 %
Rwork0.1846 80884 -
obs0.1867 85120 98.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.61 Å2
Refinement stepCycle: LAST / Resolution: 1.65→52.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5204 0 182 556 5942
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01325548
X-RAY DIFFRACTIONf_angle_d1.19967507
X-RAY DIFFRACTIONf_chiral_restr0.0754800
X-RAY DIFFRACTIONf_plane_restr0.0107970
X-RAY DIFFRACTIONf_dihedral_angle_d14.34372111
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.670.50091300.47292638X-RAY DIFFRACTION98.33
1.67-1.690.4851370.44042640X-RAY DIFFRACTION97.71
1.69-1.710.52541420.40562647X-RAY DIFFRACTION98.17
1.71-1.730.3641290.37682691X-RAY DIFFRACTION98.09
1.73-1.750.37321470.34322667X-RAY DIFFRACTION98.08
1.75-1.780.35981360.31312659X-RAY DIFFRACTION98.83
1.78-1.80.37361390.29012667X-RAY DIFFRACTION98.21
1.8-1.830.28771350.27062686X-RAY DIFFRACTION98.74
1.83-1.860.2731460.25112644X-RAY DIFFRACTION98.14
1.86-1.890.29321480.23762562X-RAY DIFFRACTION94.29
1.89-1.920.32761520.25972636X-RAY DIFFRACTION98.2
1.92-1.960.27341400.23382652X-RAY DIFFRACTION97.38
1.96-1.990.28631470.21642683X-RAY DIFFRACTION99.19
1.99-2.030.25231410.22082674X-RAY DIFFRACTION98.36
2.03-2.080.30541360.24452667X-RAY DIFFRACTION97.84
2.08-2.130.25781450.22072723X-RAY DIFFRACTION99.51
2.13-2.180.22391330.18422710X-RAY DIFFRACTION99.23
2.18-2.240.21681420.17812686X-RAY DIFFRACTION99.02
2.24-2.310.27421420.19292694X-RAY DIFFRACTION98.47
2.31-2.380.23591450.18482658X-RAY DIFFRACTION96.32
2.38-2.460.23441480.18012651X-RAY DIFFRACTION97.76
2.46-2.560.2551510.18682727X-RAY DIFFRACTION99.45
2.56-2.680.23451550.18912717X-RAY DIFFRACTION99.62
2.68-2.820.23281340.18912767X-RAY DIFFRACTION99.72
2.82-30.23261460.17892757X-RAY DIFFRACTION99.66
3-3.230.21551360.17972751X-RAY DIFFRACTION99.48
3.23-3.550.21371290.1652686X-RAY DIFFRACTION96.27
3.55-4.070.1521350.14362796X-RAY DIFFRACTION99.46
4.07-5.120.17381520.12752818X-RAY DIFFRACTION99.53
5.13-52.050.18391380.15752930X-RAY DIFFRACTION98.21
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.126402229090.21527528672-0.111370026572.224939836160.6360200595293.233948427730.0683656914981-0.1765215087060.1690139439640.0655857488049-0.0384889736305-0.0948108744737-0.1813136839270.201381838451-0.01475657214890.160643667969-0.02639313709220.02535204767240.18296887208-0.01457106126850.18671727715121.4635390527-5.82720611897-10.3355979882
23.42596377099-1.678384369710.7024375365683.7384083024-0.3767294239963.516849953210.4659625817370.624050670048-0.0140764807438-1.07106982802-0.4127001086510.1110646330870.004842402361510.363621301928-0.05461276130940.5613565861980.15244793472-0.0139370943670.367885685168-0.01990752334370.23011888093718.0748026732-24.1191758745-42.149031232
32.32670582992-0.5208486296220.5836446636241.468097073190.115268852152.305832574680.0176675427895-0.0845385440857-0.214323160040.07290052753020.09416403512510.1311838199360.16996243501-0.100075350136-0.10890821030.206253417691-0.00869984010879-0.01871671101240.2155265100550.00289652677120.21283940337423.8276775849-38.8314248174-9.27750274434
42.870619134460.2590326750520.5810965871642.31090704760.1966730353582.991693909760.0700752078292-0.179787330797-0.238865695285-0.1098476213090.0141846072030.3541183924370.243812418631-0.233573468681-0.08332581034780.208272609784-0.00641301126065-0.04597356683910.2009185656120.03670231805550.257987554772-9.49756419896-15.6431930911-26.2255902067
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 0 through 167)AA0 - 1671 - 168
22(chain 'B' and resid 0 through 167)BD0 - 1671 - 168
33(chain 'D' and resid 3 through 164)DG3 - 1642 - 163
44(chain 'C' and resid 3 through 164)CI3 - 1642 - 163

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