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- PDB-8tbl: Tricomplex of RMC-7977, KRAS G12D, and CypA -

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Basic information

Entry
Database: PDB / ID: 8tbl
TitleTricomplex of RMC-7977, KRAS G12D, 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 / lipid droplet organization / negative regulation of viral life cycle / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / virion binding / negative regulation of stress-activated MAPK cascade ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / negative regulation of viral life cycle / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / virion binding / negative regulation of stress-activated MAPK cascade / endothelial cell activation / Basigin interactions / response to mineralocorticoid / GMP binding / protein peptidyl-prolyl isomerization / forebrain astrocyte development / LRR domain binding / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / regulation of synaptic transmission, GABAergic / Uncoating of the HIV Virion / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / Early Phase of HIV Life Cycle / type I pneumocyte differentiation / Integration of provirus / negative regulation of protein phosphorylation / Rac protein signal transduction / APOBEC3G mediated resistance to HIV-1 infection / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / positive regulation of Rac protein signal transduction / Activation of RAS in B cells / myoblast proliferation / viral release from host cell / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Calcineurin activates NFAT / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / activation of protein kinase B activity / SHC1 events in ERBB4 signaling / Binding and entry of HIV virion / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of viral genome replication / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / SHC-mediated cascade:FGFR2 / negative regulation of protein kinase activity / 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:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / neutrophil chemotaxis / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / Downstream signal transduction / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation
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 domain 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 domain 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: 1.88 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)77,86010
Polymers75,0374
Non-polymers2,8236
Water12,845713
1
A: GTPase KRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9305
Polymers37,5182
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)38,9305
Polymers37,5182
Non-polymers1,4123
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.950, 83.790, 127.060
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: 19394.758 Da / Num. of mol.: 2 / Mutation: G12D
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, 719 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: obtained synthetically / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 713 / 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: 2.35 Å3/Da / Density % sol: 47.57 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 25% PEG4000, 0.1 M Tris-HCl, pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.88→63.53 Å / Num. obs: 57210 / % possible obs: 98.61 % / Redundancy: 6.7 % / Biso Wilson estimate: 25.04 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rmerge(I) obs: 0.174 / Rpim(I) all: 0.07201 / Rrim(I) all: 0.1886 / Net I/σ(I): 8.95
Reflection shellResolution: 1.88→1.947 Å / Redundancy: 6.4 % / Rmerge(I) obs: 1.867 / Mean I/σ(I) obs: 0.98 / Num. unique obs: 5573 / CC1/2: 0.321 / CC star: 0.697 / Rpim(I) all: 0.8024 / Rrim(I) all: 2.036 / % possible all: 97.51

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHASERphasing
HKL-2000data reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→63.53 Å / SU ML: 0.2314 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.9821
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2271 2743 4.8 %
Rwork0.1714 54459 -
obs0.1741 57202 98.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.47 Å2
Refinement stepCycle: LAST / Resolution: 1.88→63.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5287 0 124 713 6124
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00655588
X-RAY DIFFRACTIONf_angle_d0.82947566
X-RAY DIFFRACTIONf_chiral_restr0.0553807
X-RAY DIFFRACTIONf_plane_restr0.0049975
X-RAY DIFFRACTIONf_dihedral_angle_d14.33222134
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.910.32051360.2832651X-RAY DIFFRACTION98.06
1.91-1.950.31771080.27512674X-RAY DIFFRACTION97
1.95-1.980.33061210.24822669X-RAY DIFFRACTION97.69
1.98-2.030.27881410.23572662X-RAY DIFFRACTION98.45
2.03-2.070.27611180.22282676X-RAY DIFFRACTION97.25
2.07-2.120.27811320.20232692X-RAY DIFFRACTION98.16
2.12-2.170.29391520.21432689X-RAY DIFFRACTION98.96
2.17-2.230.24061200.19232684X-RAY DIFFRACTION98.08
2.23-2.290.25851560.19322654X-RAY DIFFRACTION98.11
2.29-2.370.23791420.18632726X-RAY DIFFRACTION98.39
2.37-2.450.27551510.17742672X-RAY DIFFRACTION98.67
2.45-2.550.26121250.18532741X-RAY DIFFRACTION98.86
2.55-2.670.25961470.1842708X-RAY DIFFRACTION98.96
2.67-2.810.26331250.17662749X-RAY DIFFRACTION99
2.81-2.980.21891310.17472752X-RAY DIFFRACTION99.07
2.98-3.210.24971410.16922729X-RAY DIFFRACTION99.14
3.21-3.540.19711420.15112770X-RAY DIFFRACTION99.35
3.54-4.050.17971480.13632784X-RAY DIFFRACTION99.63
4.05-5.10.17411570.12682818X-RAY DIFFRACTION99.7
5.1-63.530.19191500.15632959X-RAY DIFFRACTION99.52
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)
11.197776335970.224200868390.2409458852651.91714418131-0.3638969255251.417482432020.008720557822390.03689071837960.1072630020740.02974584260720.0422678920770.190745221013-0.111210744335-0.123068550916-0.04779998068050.1711162219210.01521008360750.03255725794160.1854248070840.005913409951630.21008406975844.3970962551-5.966854147019.46086706186
21.52550421421-0.6789359219710.22288629251.345051773620.2904693508141.354106775510.08536407561170.2438955682840.0372632870352-0.302034356825-0.0668803921467-0.0503434423643-0.1233863376850.0736571739555-0.01941269416320.2414272874840.0482450703270.03599147547270.1932279377120.007315638920940.15634473266117.690926483918.696419644820.9311330543
31.205159784280.189622174202-0.1669978059210.992300933226-0.2714199492661.145202753380.0712954120742-0.0314615847859-0.071648003817-0.0608037153728-0.03416754418590.1289460869220.0515903310937-0.11722751959-0.0303496472320.1921886734760.00796566172339-0.03371618598110.2007416903650.01447606313570.198130899109-10.041622408526.413083278538.6282886059
40.853572404742-0.197933305403-0.219339076950.823573135896-0.2540553561651.100765156520.0299542315965-0.0181950211498-0.0872000670431-0.05642041869140.05334044690680.01327510288780.1844127672970.0640918835953-0.06649686793610.1826683080260.00560910324825-0.05006780720120.163233516555-0.001415094565020.17658974129941.655933776-38.768860781410.1921979797
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 0 through 169)
2X-RAY DIFFRACTION2(chain 'B' and resid 0 through 169)
3X-RAY DIFFRACTION3(chain 'C' and resid 1 through 165)
4X-RAY DIFFRACTION4(chain 'D' and resid 2 through 164)

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