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- PDB-8tbm: Tricomplex of RMC-7977, KRAS G12V, and CypA -

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Basic information

Entry
Database: PDB / ID: 8tbm
TitleTricomplex of RMC-7977, KRAS G12V, 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 / negative regulation of viral life cycle / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation ...negative regulation of protein K48-linked ubiquitination / negative regulation of viral life cycle / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / virion binding / Basigin interactions / forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / cyclosporin A binding / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Rac protein signal transduction / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Integration of provirus / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / APOBEC3G mediated resistance to HIV-1 infection / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Calcineurin activates NFAT / SOS-mediated signalling / viral release from host cell / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / Binding and entry of HIV virion / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / positive regulation of viral genome replication / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / protein peptidyl-prolyl isomerization / 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:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / positive regulation of protein dephosphorylation / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / activation of protein kinase B activity / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / neutrophil chemotaxis / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / negative regulation of protein phosphorylation / VEGFR2 mediated cell proliferation / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / positive regulation of protein secretion / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity
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: 1.57 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
D: Peptidyl-prolyl cis-trans isomerase A
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,96411
Polymers75,0494
Non-polymers2,9157
Water11,223623
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9365
Polymers37,5242
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)39,0286
Polymers37,5242
Non-polymers1,5044
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.560, 84.090, 127.100
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: 19400.916 Da / Num. of mol.: 2 / Mutation: G12V
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 , 5 types, 630 molecules

#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / 5'-Guanylyl imidodiphosphate


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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: 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: obtained synthetically / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 623 / 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: 2.33 Å3/Da / Density % sol: 47.3 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 24% PEG6000, 0.1 M imidazole, pH 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 13, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.57→35.58 Å / Num. obs: 96907 / % possible obs: 98.21 % / Redundancy: 6.6 % / Biso Wilson estimate: 22.65 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.1059 / Rpim(I) all: 0.04429 / Rrim(I) all: 0.115 / Net I/σ(I): 10.67
Reflection shellResolution: 1.57→1.626 Å / Redundancy: 6.9 % / Rmerge(I) obs: 2.779 / Mean I/σ(I) obs: 0.93 / Num. unique obs: 9506 / CC1/2: 0.359 / CC star: 0.726 / Rpim(I) all: 1.136 / Rrim(I) all: 2.967 / % possible all: 97.67

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHASERphasing
HKL-2000data reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.57→35.58 Å / SU ML: 0.2432 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.238
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2107 4779 4.93 %
Rwork0.1782 92119 -
obs0.1797 96898 98.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.24 Å2
Refinement stepCycle: LAST / Resolution: 1.57→35.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5199 0 196 623 6018
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00595566
X-RAY DIFFRACTIONf_angle_d0.85947539
X-RAY DIFFRACTIONf_chiral_restr0.0565810
X-RAY DIFFRACTIONf_plane_restr0.005966
X-RAY DIFFRACTIONf_dihedral_angle_d13.95772139
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.57-1.590.41091350.34613038X-RAY DIFFRACTION97.45
1.59-1.610.33651530.34313008X-RAY DIFFRACTION97.89
1.61-1.630.38931540.32013017X-RAY DIFFRACTION97.66
1.63-1.650.33311470.31143046X-RAY DIFFRACTION97.62
1.65-1.670.31951400.28823009X-RAY DIFFRACTION97.61
1.67-1.690.3571590.27273045X-RAY DIFFRACTION98.1
1.69-1.720.30281700.26193029X-RAY DIFFRACTION98.22
1.72-1.740.28021480.24033042X-RAY DIFFRACTION98.64
1.74-1.770.28381500.24253061X-RAY DIFFRACTION97.96
1.77-1.80.29951810.22863036X-RAY DIFFRACTION99.29
1.8-1.830.25891570.22073042X-RAY DIFFRACTION97.83
1.83-1.860.26021650.22473054X-RAY DIFFRACTION98.65
1.86-1.90.26511540.20052877X-RAY DIFFRACTION93.2
1.9-1.940.21321700.23053X-RAY DIFFRACTION98.29
1.94-1.980.21391380.19333091X-RAY DIFFRACTION98.96
1.98-2.020.19991670.18443067X-RAY DIFFRACTION99.2
2.02-2.070.21591650.19053078X-RAY DIFFRACTION98.69
2.07-2.130.20911650.17973064X-RAY DIFFRACTION98.72
2.13-2.190.23141770.18663046X-RAY DIFFRACTION98.62
2.19-2.260.22471560.1783120X-RAY DIFFRACTION99.09
2.26-2.350.2381360.17653113X-RAY DIFFRACTION98.99
2.35-2.440.19811840.17813084X-RAY DIFFRACTION99.24
2.44-2.550.21921480.18763127X-RAY DIFFRACTION99.3
2.55-2.680.21571660.19572945X-RAY DIFFRACTION94.65
2.68-2.850.26011520.18193122X-RAY DIFFRACTION98.79
2.85-3.070.21011840.1693109X-RAY DIFFRACTION99.43
3.07-3.380.18871800.16033134X-RAY DIFFRACTION99.52
3.38-3.870.17931570.14373209X-RAY DIFFRACTION99.67
3.87-4.870.14751590.13043201X-RAY DIFFRACTION99.14
4.87-35.580.17531620.16153252X-RAY DIFFRACTION96.36
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)
12.14258050482-0.7422932041410.2432830655283.598454290980.1722658049622.320723944930.0466919816999-0.007593344750530.252112823456-0.01521411754980.0160089584684-0.361310979706-0.2132598332270.263583850352-0.05648937702660.154116297778-0.03036977675480.04371206214370.165273104348-0.01527980359830.19805471416321.4578551239-5.8373596316-9.85129166534
23.42070462923-1.132574506880.1756869391642.97117997739-0.2779835581823.224087362460.1632883591690.3953958934190.0813238284657-0.559501847768-0.1326995783340.0505976923854-0.137193876979-0.00920542028453-0.02476285797440.2600299098630.03011126469710.003586839925790.182360287952-0.00172636045690.17285111107117.3116752037-23.6022425095-42.5947237278
32.266221681060.1699398584160.373165446121.49854298614-0.03827093541962.254409784530.006600722185090.00482346322781-0.12467665110.1181227612560.03366345077280.02283699705770.216268035048-0.108742834383-0.04402952066320.164606542739-0.00651672146593-0.003898586865010.113988251777-0.0154301290780.11626593310224.1974672798-39.1966972981-10.2188925607
42.955764560660.5136711608510.3929148381942.0326304265-0.4622858819142.247635997380.0881000804099-0.187654657827-0.07320386208030.027443857898-0.06260525562630.0614985682460.0622852827426-0.150571766599-0.02458228408620.1285962418720.008734303690180.003507403747580.1462311268780.0009098100061520.124892762471-10.0819603292-15.6542384391-24.8121175387
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 0 through 167)
2X-RAY DIFFRACTION2(chain 'B' and resid 0 through 167)
3X-RAY DIFFRACTION3(chain 'D' and resid 3 through 165)
4X-RAY DIFFRACTION4(chain 'C' and resid 1 through 165)

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