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- PDB-8g9p: Tricomplex of RMC-4998, KRAS G12C, and CypA -

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Basic information

Entry
Database: PDB / ID: 8g9p
TitleTricomplex of RMC-4998, 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 / 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-like / Cyclophilin / 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 ...Cyclophilin-like / Cyclophilin / 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 nucleotide triphosphate hydrolases / Beta Barrel / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Chem-YV2 / GTPase KRas / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsTomlinson, A.C.A. / Saldajeno-Concar, M. / 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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)78,19112
Polymers75,0574
Non-polymers3,1348
Water17,997999
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0966
Polymers37,5292
Non-polymers1,5674
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-32 kcal/mol
Surface area14910 Å2
MethodPISA
2
B: GTPase KRas
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0966
Polymers37,5292
Non-polymers1,5674
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2730 Å2
ΔGint-32 kcal/mol
Surface area15110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.030, 101.760, 66.360
Angle α, β, γ (deg.)90.000, 91.040, 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 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 , 5 types, 1007 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-YV2 / (2S)-2-{(5S)-7-[(2E)-4-(dimethylamino)-4-methylpent-2-enoyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl}-N-[(1P,8S,10R,14S,21M)-22-ethyl-21-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1~2,6~.1~10,14~.0~23,27~]nonacosa-1(25),2(29),3,5,20,23,26-heptaen-8-yl]-3-methylbutanamide (non-preferred name)


Mass: 985.263 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C57H76N8O7 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 999 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 43.06 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 22% PEG 3350, 100 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03317 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 23, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03317 Å / Relative weight: 1
ReflectionResolution: 1.5→43.43 Å / Num. obs: 94582 / % possible obs: 93.01 % / Redundancy: 4.1 % / Biso Wilson estimate: 15.76 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.05936 / Rpim(I) all: 0.03313 / Rrim(I) all: 0.06815 / Net I/σ(I): 12.55
Reflection shellResolution: 1.5→1.554 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.3282 / Mean I/σ(I) obs: 3.44 / Num. unique obs: 8308 / CC1/2: 0.918 / CC star: 0.978 / Rpim(I) all: 0.1834 / Rrim(I) all: 0.3769 / % possible all: 82.35

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→43.43 Å / SU ML: 0.1375 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.6421
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1875 4754 5.03 %
Rwork0.1563 89820 -
obs0.1579 94574 93.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.03 Å2
Refinement stepCycle: LAST / Resolution: 1.5→43.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5247 0 212 999 6458
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00915768
X-RAY DIFFRACTIONf_angle_d1.21547829
X-RAY DIFFRACTIONf_chiral_restr0.0652830
X-RAY DIFFRACTIONf_plane_restr0.01061017
X-RAY DIFFRACTIONf_dihedral_angle_d14.30792186
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.520.2052940.18952273X-RAY DIFFRACTION71.75
1.52-1.530.23841370.18282697X-RAY DIFFRACTION83.3
1.53-1.550.21771770.17712927X-RAY DIFFRACTION91.75
1.55-1.570.2321660.17222925X-RAY DIFFRACTION92.02
1.57-1.590.23131970.16752979X-RAY DIFFRACTION93.85
1.59-1.620.21721530.16813058X-RAY DIFFRACTION94.55
1.62-1.640.21481590.16943032X-RAY DIFFRACTION94.86
1.64-1.660.21081610.16223071X-RAY DIFFRACTION94.36
1.66-1.690.18791580.1573001X-RAY DIFFRACTION94.33
1.69-1.720.19071580.16153046X-RAY DIFFRACTION94.49
1.72-1.750.20291790.16092984X-RAY DIFFRACTION93.89
1.75-1.780.23511620.1993011X-RAY DIFFRACTION93.6
1.78-1.810.24941730.19032984X-RAY DIFFRACTION93.46
1.81-1.850.18611460.18662969X-RAY DIFFRACTION91.08
1.85-1.890.21351510.17592648X-RAY DIFFRACTION83.7
1.89-1.930.21481530.15583097X-RAY DIFFRACTION95.84
1.93-1.980.18211590.15183077X-RAY DIFFRACTION95.91
1.98-2.040.18621380.1583125X-RAY DIFFRACTION96.23
2.04-2.10.19671520.15313121X-RAY DIFFRACTION96.26
2.1-2.160.20531550.16223095X-RAY DIFFRACTION96.21
2.16-2.240.1851870.16553068X-RAY DIFFRACTION96.27
2.24-2.330.1941630.15413104X-RAY DIFFRACTION95.92
2.33-2.440.18471580.16373074X-RAY DIFFRACTION95.28
2.44-2.560.2081340.16143008X-RAY DIFFRACTION92.6
2.56-2.730.18741630.16712816X-RAY DIFFRACTION88.01
2.73-2.940.18591700.16313148X-RAY DIFFRACTION97.53
2.94-3.230.19471700.15613170X-RAY DIFFRACTION97.63
3.23-3.70.14281510.1353171X-RAY DIFFRACTION97.11
3.7-4.660.14291600.12763057X-RAY DIFFRACTION94.2
4.66-43.430.18751700.15063084X-RAY DIFFRACTION93.91
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)
11.17637658108-0.164115243144-0.5151115319470.627124455386-0.2547488177421.389222015380.06551010984010.06906073540840.0396726356499-0.0708916483811-0.014311126865-0.0326225131909-0.1116427451920.0199685987494-0.05917180246320.139062974756-0.006672871996840.02602455157430.0963975546492-0.01096066468860.12970996169821.0207667664-13.97458251841.63362866658
20.788140434940.3317298928430.4213173369591.20082024505-0.1150153120121.198952103990.03309419174870.0148257447939-0.04243539783830.02019199717810.0325001923158-0.02249895451130.02101676581510.00574673983009-0.06683112672240.1064810690280.003024830457630.01983264618730.0952251162805-0.005466825931090.15369570712320.3610762851-31.778463255228.8680672931
31.06183034086-0.00817270714664-0.1163754700090.9349568052740.1978033405751.28023895341-0.01090660802010.02356331490510.080904666040.0459607091984-0.0106729198177-0.030477550177-0.01392185057020.05038285880670.01963108687510.0993686339834-0.00711254098720.01569472808810.08006076955070.0101690278020.14041353932942.9070753951-7.9819044501934.612563625
40.996711010114-0.131537724230.2796648299011.042552715850.3105154434181.4669154235-0.0316296919448-0.0528173477168-0.09306149444410.01161449586250.0453343169556-0.02459455707480.08171726651270.0626986051235-0.01444528598770.1300983323120.01230073677570.02504943497730.10760381370.00285643868040.16040901037244.1507763062-37.9203955464-4.77369109485
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain AAA - C0 - 3011
22chain BBD - F0 - 3011
33chain CCG2 - 1651 - 164
44Chain DDH0 - 1651 - 166

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