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- PDB-8tbg: Tricomplex of RMC-7977, HRAS WT, and CypA -

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Basic information

Entry
Database: PDB / ID: 8tbg
TitleTricomplex of RMC-7977, HRAS WT, and CypA
Components
  • GTPase HRas
  • 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 / GTPase complex / virion binding / leukocyte chemotaxis ...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 / GTPase complex / virion binding / leukocyte chemotaxis / oncogene-induced cell senescence / positive regulation of ruffle assembly / endothelial cell activation / negative regulation of stress-activated MAPK cascade / Basigin interactions / negative regulation of GTPase activity / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of miRNA metabolic process / cyclosporin A binding / T-helper 1 type immune response / positive regulation of wound healing / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / defense response to protozoan / Early Phase of HIV Life Cycle / 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 / protein peptidyl-prolyl isomerization / 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 / GRB2 events in EGFR signaling / EGFR Transactivation by Gastrin / SHC1 events in EGFR signaling / positive regulation of protein targeting to membrane / Signalling to RAS / GRB2 events in ERBB2 signaling / Binding and entry of HIV virion / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / adipose tissue development / SHC1 events in ERBB2 signaling / 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 / Schwann cell development / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / positive regulation of epithelial cell proliferation / Signaling by FLT3 ITD and TKD mutants / : / FRS-mediated FGFR2 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / EPHB-mediated forward signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / myelination / Signaling by FGFR1 in disease / neutrophil chemotaxis / 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 / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / intrinsic apoptotic signaling pathway / Signaling by ERBB2 TMD/JMD mutants / small monomeric GTPase / positive regulation of MAP kinase activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / positive regulation of GTPase activity / VEGFR2 mediated cell proliferation / negative regulation of protein phosphorylation
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. / Rho (Ras homology) subfamily of Ras-like 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. / 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 HRas / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsChen, A. / Tomlinson, A.C.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 HRas
B: GTPase HRas
C: Peptidyl-prolyl cis-trans isomerase A
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,02711
Polymers74,1124
Non-polymers2,9157
Water15,241846
1
A: GTPase HRas
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4675
Polymers37,0562
Non-polymers1,4123
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase HRas
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5606
Polymers37,0562
Non-polymers1,5044
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.450, 80.860, 128.209
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 HRas / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18932.242 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#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, 853 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 846 / 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: 2.29 Å3/Da / Density % sol: 46.26 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 28% PEG4000, 0.1 M Tris, pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.95371 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 5, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95371 Å / Relative weight: 1
ReflectionResolution: 1.2→58.29 Å / Num. obs: 211361 / % possible obs: 99.54 % / Redundancy: 7.1 % / Biso Wilson estimate: 13.4 Å2 / CC1/2: 0.998 / CC star: 0.999 / Rmerge(I) obs: 0.09715 / Rpim(I) all: 0.03855 / Rrim(I) all: 0.1047 / Net I/σ(I): 8.22
Reflection shellResolution: 1.2→1.243 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.725 / Mean I/σ(I) obs: 0.82 / Num. unique obs: 20454 / CC1/2: 0.357 / CC star: 0.725 / Rpim(I) all: 0.8112 / Rrim(I) all: 1.828 / % possible all: 97.18

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→58.29 Å / SU ML: 0.1604 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 19.9101
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1918 10617 5.03 %
Rwork0.1606 200524 -
obs0.1622 211141 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.72 Å2
Refinement stepCycle: LAST / Resolution: 1.2→58.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5178 0 196 846 6220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00575686
X-RAY DIFFRACTIONf_angle_d0.89597723
X-RAY DIFFRACTIONf_chiral_restr0.079817
X-RAY DIFFRACTIONf_plane_restr0.00521005
X-RAY DIFFRACTIONf_dihedral_angle_d13.58012185
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.210.37153090.3256410X-RAY DIFFRACTION95.58
1.21-1.230.34153430.30496467X-RAY DIFFRACTION97.59
1.23-1.240.32043770.28636520X-RAY DIFFRACTION98.22
1.24-1.260.29083420.27586498X-RAY DIFFRACTION97.78
1.26-1.280.30613350.26856617X-RAY DIFFRACTION99.77
1.28-1.290.31063650.25636646X-RAY DIFFRACTION99.67
1.29-1.310.27433650.23436642X-RAY DIFFRACTION99.7
1.31-1.330.273430.22316646X-RAY DIFFRACTION99.81
1.33-1.350.25223640.21516645X-RAY DIFFRACTION99.76
1.35-1.370.2413590.20596626X-RAY DIFFRACTION99.73
1.37-1.40.23483420.19196688X-RAY DIFFRACTION99.86
1.4-1.420.23183630.19036666X-RAY DIFFRACTION99.83
1.42-1.450.25153300.18526640X-RAY DIFFRACTION99.83
1.45-1.480.21943250.1796695X-RAY DIFFRACTION99.89
1.48-1.510.22253570.17136674X-RAY DIFFRACTION99.89
1.51-1.550.1993520.16296683X-RAY DIFFRACTION99.8
1.55-1.590.19033750.14836676X-RAY DIFFRACTION99.99
1.59-1.630.20013470.13936693X-RAY DIFFRACTION99.93
1.63-1.680.18123480.13796703X-RAY DIFFRACTION99.86
1.68-1.730.19173530.14046690X-RAY DIFFRACTION99.9
1.73-1.790.17593690.13216700X-RAY DIFFRACTION99.97
1.79-1.860.17853680.13786682X-RAY DIFFRACTION99.97
1.86-1.950.16983420.1396752X-RAY DIFFRACTION99.96
1.95-2.050.16423470.13326748X-RAY DIFFRACTION99.96
2.05-2.180.16473630.13566748X-RAY DIFFRACTION99.99
2.18-2.350.17063550.14016756X-RAY DIFFRACTION99.99
2.35-2.590.18153670.15366776X-RAY DIFFRACTION99.94
2.59-2.960.18873770.15976817X-RAY DIFFRACTION100
2.96-3.730.16933560.15396880X-RAY DIFFRACTION99.97
3.73-58.290.17163790.15137140X-RAY DIFFRACTION99.95

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