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- PDB-8g9q: Tricomplex of Compound-1, KRAS G12C, and CypA -

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Basic information

Entry
Database: PDB / ID: 8g9q
TitleTricomplex of Compound-1, KRAS G12C, 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 / 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 / virion binding / leukocyte chemotaxis / 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 / virion binding / leukocyte chemotaxis / endothelial cell activation / negative regulation of stress-activated MAPK cascade / Basigin interactions / forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / Rac protein signal transduction / Early Phase of HIV Life Cycle / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / viral release from host cell / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Calcineurin activates NFAT / protein peptidyl-prolyl isomerization / 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 / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / positive regulation of viral genome replication / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / : / 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 / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / neutrophil chemotaxis / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / activation of protein kinase B activity / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / G protein activity / VEGFR2 mediated cell proliferation / negative regulation of protein phosphorylation / platelet aggregation / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / positive regulation of protein secretion / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants
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 / Chem-YV6 / GTPase KRas / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsTomlinson, A.C.A. / Chen, A. / Knox, J.E. / Yano, J.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Science / Year: 2023
Title: Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Authors: Schulze, C.J. / Seamon, K.J. / Zhao, Y. / Yang, Y.C. / Cregg, J. / Kim, D. / Tomlinson, A. / Choy, T.J. / Wang, Z. / Sang, B. / Pourfarjam, Y. / Lucas, J. / Cuevas-Navarro, A. / Ayala- ...Authors: Schulze, C.J. / Seamon, K.J. / Zhao, Y. / Yang, Y.C. / Cregg, J. / Kim, D. / Tomlinson, A. / Choy, T.J. / Wang, Z. / Sang, B. / Pourfarjam, Y. / Lucas, J. / Cuevas-Navarro, A. / Ayala-Santos, C. / Vides, A. / Li, C. / Marquez, A. / Zhong, M. / Vemulapalli, V. / Weller, C. / Gould, A. / Whalen, D.M. / Salvador, A. / Milin, A. / Saldajeno-Concar, M. / Dinglasan, N. / Chen, A. / Evans, J. / Knox, J.E. / Koltun, E.S. / Singh, M. / Nichols, R. / Wildes, D. / Gill, A.L. / Smith, J.A.M. / Lito, P.
History
DepositionFeb 21, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: Database references / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity.pdbx_description / _entity.pdbx_ec ..._entity.pdbx_description / _entity.pdbx_ec / _entity_src_gen.pdbx_gene_src_gene / _struct_ref.db_code / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_db_isoform / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq_dif.pdbx_seq_db_accession_code
Revision 1.2Aug 30, 2023Group: 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: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6555
Polymers37,4902
Non-polymers1,1643
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.159, 100.689, 47.776
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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Protein , 2 types, 2 molecules AD

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


Mass: 19382.811 Da / Num. of mol.: 1 / 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: 18107.516 Da / Num. of mol.: 1
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, 361 molecules

#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-YV6 / methyl (3S)-1-(N-{4-[(pyridin-2-yl)disulfanyl]butanoyl}-L-valyl-3-hydroxy-L-phenylalanyl)-1,2-diazinane-3-carboxylate


Mass: 617.780 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H39N5O6S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / 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: 2.15 Å3/Da / Density % sol: 42.91 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 22% PEG 3350, 100 mM NaCl, 100 mM Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 30, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.4→36.31 Å / Num. obs: 63411 / % possible obs: 97.96 % / Redundancy: 6.6 % / Biso Wilson estimate: 18.79 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.07486 / Rpim(I) all: 0.03128 / Rrim(I) all: 0.08131 / Net I/σ(I): 9.31
Reflection shellResolution: 1.4→1.45 Å / Redundancy: 6.3 % / Rmerge(I) obs: 1.026 / Mean I/σ(I) obs: 1 / Num. unique obs: 6055 / CC1/2: 0.749 / CC star: 0.925 / Rpim(I) all: 0.4342 / Rrim(I) all: 1.117 / % possible all: 95.19

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.4→36.31 Å / SU ML: 0.1969 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.8262
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.214 3206 5.06 %
Rwork0.1864 60205 -
obs0.1878 63411 97.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.18 Å2
Refinement stepCycle: LAST / Resolution: 1.4→36.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2618 0 68 358 3044
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00462797
X-RAY DIFFRACTIONf_angle_d0.77283782
X-RAY DIFFRACTIONf_chiral_restr0.0774405
X-RAY DIFFRACTIONf_plane_restr0.0053494
X-RAY DIFFRACTIONf_dihedral_angle_d14.43661043
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.44521290.42852218X-RAY DIFFRACTION85.63
1.42-1.440.42541230.36792603X-RAY DIFFRACTION96.84
1.44-1.460.27961330.27062583X-RAY DIFFRACTION98.02
1.46-1.490.2791230.27432592X-RAY DIFFRACTION96.76
1.49-1.520.31911520.23782554X-RAY DIFFRACTION98.47
1.52-1.550.23331260.22412610X-RAY DIFFRACTION96.85
1.55-1.580.23971470.20542602X-RAY DIFFRACTION98.81
1.58-1.610.25851420.20132582X-RAY DIFFRACTION98.13
1.61-1.650.22611340.19082622X-RAY DIFFRACTION97.7
1.65-1.690.2011470.19312637X-RAY DIFFRACTION99.43
1.69-1.740.21641370.19672466X-RAY DIFFRACTION93.26
1.74-1.790.24241610.21372579X-RAY DIFFRACTION97.86
1.79-1.840.23541390.20812626X-RAY DIFFRACTION98.61
1.84-1.910.23811380.22522662X-RAY DIFFRACTION98.9
1.91-1.990.24871450.21132647X-RAY DIFFRACTION99.36
1.99-2.080.19671360.18312654X-RAY DIFFRACTION98.97
2.08-2.190.21931500.18362655X-RAY DIFFRACTION99.36
2.19-2.320.22951140.20142707X-RAY DIFFRACTION99.4
2.32-2.50.22651540.18422579X-RAY DIFFRACTION95.86
2.5-2.750.221490.18592688X-RAY DIFFRACTION99.75
2.75-3.150.21651390.17972736X-RAY DIFFRACTION99.9
3.15-3.970.17991270.15722773X-RAY DIFFRACTION99.59
3.97-36.310.16991610.1542830X-RAY DIFFRACTION98.13
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)
12.926156396870.1554096002590.2585476789891.67724327349-0.6498705079532.96593927406-0.2503908358220.1496974820330.0691264083091-0.03387365059860.1327194025460.0152438334668-0.0491609901839-0.1344495610630.08607601446140.152299109981-0.0322142335101-0.01159814743990.148268050391-0.0005098551513030.142498306632-14.2010268479.56932898776-23.0562674534
23.24473018866-0.230104539213-0.4695867653482.209171943410.4283218949011.85672951155-0.0106556003882-0.0498925896947-0.2206499732910.084356990195-0.02452552697120.1137385579680.139270726549-0.03246331213970.00409200176220.137191358288-0.02461691587360.006457262122210.1239190771430.007589715107760.12300842707-19.8215060044-14.56923785-45.2704864929
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain A and resseq 0:301)AA - C0 - 3011
22(chain D and resseq 3:165)DD3 - 1652 - 164

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