+Open data
-Basic information
Entry | Database: PDB / ID: 8tbl | ||||||
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Title | Tricomplex of RMC-7977, KRAS G12D, and CypA | ||||||
Components |
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Keywords | HYDROLASE/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 / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å | ||||||
Authors | Tomlinson, A.C.A. / Chen, A. / Knox, J.E. / Yano, J.K. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8tbl.cif.gz | 354.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8tbl.ent.gz | 236.8 KB | Display | PDB format |
PDBx/mmJSON format | 8tbl.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8tbl_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8tbl_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8tbl_validation.xml.gz | 34.5 KB | Display | |
Data in CIF | 8tbl_validation.cif.gz | 50.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tb/8tbl ftp://data.pdbj.org/pub/pdb/validation_reports/tb/8tbl | HTTPS FTP |
-Related structure data
Related structure data | 8tbfC 8tbgC 8tbhC 8tbiC 8tbjC 8tbkC 8tbmC 8tbnC C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
-Protein , 2 types, 4 molecules ABCD
#1: Protein | 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 | 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 | #4: Chemical | #5: Chemical | Mass: 865.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H60N8O6S / Feature type: SUBJECT OF INVESTIGATION #6: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.35 Å3/Da / Density % sol: 47.57 % |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 25% PEG4000, 0.1 M Tris-HCl, pH 8.0 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 1, 2023 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97741 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 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 |
-Processing
Software |
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Refinement | Method 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
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 30.47 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.88→63.53 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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