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- PDB-8tbk: Tricomplex of RMC-7977, KRAS G12C, and CypA -

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Basic information

Entry
Database: PDB / ID: 8tbk
TitleTricomplex of RMC-7977, KRAS G12C, and CypA
Components
  • GTPase KRas
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsHYDROLASE/INHIBITOR / inhibitor / complex / small GTPase / cancer / tricomplex / 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 / 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: 1.26 Å
AuthorsTomlinson, A.C.A. / Chen, A. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2024
Title: Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.
Authors: Holderfield, M. / Lee, B.J. / Jiang, J. / Tomlinson, A. / Seamon, K.J. / Mira, A. / Patrucco, E. / Goodhart, G. / Dilly, J. / Gindin, Y. / Dinglasan, N. / Wang, Y. / Lai, L.P. / Cai, S. / ...Authors: Holderfield, M. / Lee, B.J. / Jiang, J. / Tomlinson, A. / Seamon, K.J. / Mira, A. / Patrucco, E. / Goodhart, G. / Dilly, J. / Gindin, Y. / Dinglasan, N. / Wang, Y. / Lai, L.P. / Cai, S. / Jiang, L. / Nasholm, N. / Shifrin, N. / Blaj, C. / Shah, H. / Evans, J.W. / Montazer, N. / Lai, O. / Shi, J. / Ahler, E. / Quintana, E. / Chang, S. / Salvador, A. / Marquez, A. / Cregg, J. / Liu, Y. / Milin, A. / Chen, A. / Ziv, T.B. / Parsons, D. / Knox, J.E. / Klomp, J.E. / Roth, J. / Rees, M. / Ronan, M. / Cuevas-Navarro, A. / Hu, F. / Lito, P. / Santamaria, D. / Aguirre, A.J. / Waters, A.M. / Der, C.J. / Ambrogio, C. / Wang, Z. / Gill, A.L. / Koltun, E.S. / Smith, J.A.M. / Wildes, D. / Singh, M.
History
DepositionJun 28, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 5, 2024Group: 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 KRas
B: 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)77,88010
Polymers75,0574
Non-polymers2,8236
Water17,727984
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9405
Polymers37,5292
Non-polymers1,4123
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)38,9405
Polymers37,5292
Non-polymers1,4123
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.470, 83.570, 126.210
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 KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19404.928 Da / Num. of mol.: 2 / Mutation: G12C
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, 990 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-ZNI / (1R,5S,6r)-N-[(1P,7S,9S,13S,20M)-20-{5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-21-ethyl-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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide / RMC-7977


Mass: 865.094 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 984 / 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: 2.31 Å3/Da / Density % sol: 46.74 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 27% PEG4000, 0.1 M imidazole, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.95375 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 16, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95375 Å / Relative weight: 1
ReflectionResolution: 1.26→39.92 Å / Num. obs: 183467 / % possible obs: 98.27 % / Redundancy: 7.6 % / Biso Wilson estimate: 16.69 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.07469 / Rpim(I) all: 0.02889 / Rrim(I) all: 0.08023 / Net I/σ(I): 11.03
Reflection shellResolution: 1.26→1.305 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.949 / Num. unique obs: 17699 / CC1/2: 0.367 / CC star: 0.733 / Rpim(I) all: 0.7523 / Rrim(I) all: 2.092 / % possible all: 95.69

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHASERphasing
HKL-2000data reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.26→39.92 Å / SU ML: 0.1449 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.7552
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1839 9267 5.05 %
Rwork0.1462 174189 -
obs0.1481 183456 98.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.86 Å2
Refinement stepCycle: LAST / Resolution: 1.26→39.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5242 0 190 984 6416
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00545658
X-RAY DIFFRACTIONf_angle_d0.86757667
X-RAY DIFFRACTIONf_chiral_restr0.0797814
X-RAY DIFFRACTIONf_plane_restr0.0054996
X-RAY DIFFRACTIONf_dihedral_angle_d14.41682176
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.26-1.270.34572890.30545520X-RAY DIFFRACTION94.56
1.27-1.290.30112950.28575593X-RAY DIFFRACTION95.62
1.29-1.310.30492940.2695704X-RAY DIFFRACTION96.88
1.31-1.320.30182810.25995654X-RAY DIFFRACTION96.91
1.32-1.340.28322910.24755700X-RAY DIFFRACTION96.88
1.34-1.360.27933370.23085643X-RAY DIFFRACTION97.35
1.36-1.380.26883130.22795708X-RAY DIFFRACTION97.38
1.38-1.40.26612810.21255755X-RAY DIFFRACTION97.4
1.4-1.420.2462860.20015722X-RAY DIFFRACTION97.42
1.42-1.440.24163020.18745722X-RAY DIFFRACTION97.95
1.44-1.470.21732920.17275780X-RAY DIFFRACTION97.97
1.47-1.490.21413180.15815731X-RAY DIFFRACTION97.72
1.49-1.520.18263160.15155725X-RAY DIFFRACTION97.86
1.52-1.550.18773230.14115775X-RAY DIFFRACTION98.48
1.55-1.590.18783030.13825783X-RAY DIFFRACTION98.48
1.59-1.620.17163500.12925733X-RAY DIFFRACTION98.57
1.62-1.670.17743230.12635807X-RAY DIFFRACTION98.68
1.67-1.710.17653110.1345814X-RAY DIFFRACTION98.58
1.71-1.760.19033510.13785782X-RAY DIFFRACTION98.74
1.76-1.820.17292880.13435845X-RAY DIFFRACTION98.78
1.82-1.880.17043020.12725842X-RAY DIFFRACTION99.26
1.88-1.960.16593130.12375884X-RAY DIFFRACTION99.39
1.96-2.050.16843350.12795881X-RAY DIFFRACTION99.2
2.05-2.150.17912830.13515916X-RAY DIFFRACTION99.73
2.15-2.290.17322810.13845956X-RAY DIFFRACTION99.6
2.29-2.470.17833370.13995945X-RAY DIFFRACTION99.79
2.47-2.710.17472990.14955975X-RAY DIFFRACTION99.78
2.71-3.110.18633210.14865999X-RAY DIFFRACTION99.83
3.11-3.910.17153190.13276032X-RAY DIFFRACTION99.56
3.91-39.920.16653330.13826263X-RAY DIFFRACTION99.53

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