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Yorodumi- PDB-7z6l: Crystal structure of PROTAC 5 in complex with the bromodomain of ... -
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-Basic information
Entry | Database: PDB / ID: 7z6l | |||||||||||||||
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Title | Crystal structure of PROTAC 5 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB | |||||||||||||||
Components |
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Keywords | LIGASE / bromodomain / PROTAC complex / E3 ligase | |||||||||||||||
Function / homology | Function and homology information bBAF complex / npBAF complex / nBAF complex / brahma complex / regulation of cellular response to hypoxia / GBAF complex / regulation of G0 to G1 transition / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / regulation of nucleotide-excision repair ...bBAF complex / npBAF complex / nBAF complex / brahma complex / regulation of cellular response to hypoxia / GBAF complex / regulation of G0 to G1 transition / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / regulation of nucleotide-excision repair / target-directed miRNA degradation / transcription elongation factor activity / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / regulation of mitotic metaphase/anaphase transition / SWI/SNF complex / Cul5-RING ubiquitin ligase complex / positive regulation of double-strand break repair / ATP-dependent chromatin remodeler activity / positive regulation of T cell differentiation / intermediate filament cytoskeleton / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / positive regulation of stem cell population maintenance / SUMOylation of ubiquitinylation proteins / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / Regulation of MITF-M-dependent genes involved in pigmentation / negative regulation of transcription elongation by RNA polymerase II / regulation of G1/S transition of mitotic cell cycle / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of cell differentiation / spermatid development / ubiquitin-like ligase-substrate adaptor activity / Tat-mediated elongation of the HIV-1 transcript / positive regulation of myoblast differentiation / Formation of HIV-1 elongation complex containing HIV-1 Tat / ATP-dependent activity, acting on DNA / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / helicase activity / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / transcription elongation by RNA polymerase II / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / Vif-mediated degradation of APOBEC3G / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / negative regulation of cell growth / Evasion by RSV of host interferon responses / RMTs methylate histone arginines / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / nervous system development / Replication of the SARS-CoV-2 genome / protein-macromolecule adaptor activity / histone binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / amyloid fibril formation / molecular adaptor activity / transcription coactivator activity / transcription cis-regulatory region binding / protein stabilization / hydrolase activity / protein ubiquitination / chromatin remodeling / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / negative regulation of gene expression / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / positive regulation of cell population proliferation / chromatin binding / regulation of DNA-templated transcription / negative regulation of apoptotic process / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.24 Å | |||||||||||||||
Authors | Roy, M.J. / Bader, G. / Farnaby, W. / Ciulli, A. | |||||||||||||||
Funding support | Austria, United Kingdom, 4items
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Citation | Journal: Nat Commun / Year: 2022 Title: A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Authors: Kofink, C. / Trainor, N. / Mair, B. / Wohrle, S. / Wurm, M. / Mischerikow, N. / Roy, M.J. / Bader, G. / Greb, P. / Garavel, G. / Diers, E. / McLennan, R. / Whitworth, C. / Vetma, V. / ...Authors: Kofink, C. / Trainor, N. / Mair, B. / Wohrle, S. / Wurm, M. / Mischerikow, N. / Roy, M.J. / Bader, G. / Greb, P. / Garavel, G. / Diers, E. / McLennan, R. / Whitworth, C. / Vetma, V. / Rumpel, K. / Scharnweber, M. / Fuchs, J.E. / Gerstberger, T. / Cui, Y. / Gremel, G. / Chetta, P. / Hopf, S. / Budano, N. / Rinnenthal, J. / Gmaschitz, G. / Mayer, M. / Koegl, M. / Ciulli, A. / Weinstabl, H. / Farnaby, W. | |||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7z6l.cif.gz | 205.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7z6l.ent.gz | 160.1 KB | Display | PDB format |
PDBx/mmJSON format | 7z6l.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7z6l_validation.pdf.gz | 867.4 KB | Display | wwPDB validaton report |
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Full document | 7z6l_full_validation.pdf.gz | 868.7 KB | Display | |
Data in XML | 7z6l_validation.xml.gz | 18.1 KB | Display | |
Data in CIF | 7z6l_validation.cif.gz | 25.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/z6/7z6l ftp://data.pdbj.org/pub/pdb/validation_reports/z6/7z6l | HTTPS FTP |
-Related structure data
Related structure data | 7z76C 7z77C 7z78C 5t35S S: Starting model for refinement 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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Unit cell |
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-Components
-Protein , 4 types, 4 molecules ABCD
#1: Protein | Mass: 14380.542 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SMARCA2, BAF190B, BRM, SNF2A, SNF2L2 / Plasmid: pDEST15 / Production host: Escherichia coli BL21(DE3) (bacteria) References: UniProt: P51531, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement |
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#2: Protein | Mass: 18702.291 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Plasmid: pHAT4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337 |
#3: Protein | Mass: 10974.616 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Plasmid: pCDFDuet / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369 |
#4: Protein | Mass: 11748.406 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Plasmid: pCDFDuet / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15370 |
-Non-polymers , 2 types, 65 molecules
#5: Chemical | ChemComp-IEI / ( |
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#6: Water | ChemComp-HOH / |
-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: 2.15 Å3/Da / Density % sol: 42.9 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 Details: 33% (v/v) glycerol ethoxylate, 0.2 M ammonium chloride, 0.1 M HEPES, pH 7.5 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 18, 2018 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.9686 Å / Relative weight: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 2.24→48.54 Å / Num. obs: 22540 / % possible obs: 99.3 % / Redundancy: 6.48 % / Biso Wilson estimate: 46.64 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.123 / Rrim(I) all: 0.134 / Χ2: 1.029 / Net I/σ(I): 10.41 / Num. measured all: 146056 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Phasing
Phasing | Method: molecular replacement |
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 5t35 Resolution: 2.24→48.54 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.914 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.297 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.279 / SU Rfree Blow DPI: 0.205 / SU Rfree Cruickshank DPI: 0.212
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Displacement parameters | Biso max: 144.31 Å2 / Biso mean: 52.75 Å2 / Biso min: 22.03 Å2
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Refine analyze | Luzzati coordinate error obs: 0.29 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 2.24→48.54 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.24→2.35 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
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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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