[English] 日本語
Yorodumi
- PDB-7z6l: Crystal structure of PROTAC 5 in complex with the bromodomain of ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7z6l
TitleCrystal structure of PROTAC 5 in complex with the bromodomain of human SMARCA2 and pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • Probable global transcription activator SNF2L2
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / bromodomain / PROTAC complex / E3 ligase
Function / homology
Function and homology information


bBAF complex / npBAF complex / brahma complex / nBAF 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 / transcription elongation factor activity ...bBAF complex / npBAF complex / brahma complex / nBAF 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 / transcription elongation factor activity / regulation of nucleotide-excision repair / target-directed miRNA degradation / elongin complex / VCB complex / SWI/SNF complex / ATP-dependent chromatin remodeler activity / regulation of mitotic metaphase/anaphase transition / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / positive regulation of double-strand break repair / positive regulation of T cell differentiation / intermediate filament cytoskeleton / Cul2-RING ubiquitin ligase complex / positive regulation of stem cell population maintenance / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / negative regulation of transcription elongation by RNA polymerase II / spermatid development / regulation of G1/S transition of mitotic cell cycle / negative regulation of cell differentiation / 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 / ubiquitin-like ligase-substrate adaptor activity / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / positive regulation of myoblast differentiation / 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 / helicase activity / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / Vif-mediated degradation of APOBEC3G / cell morphogenesis / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / negative regulation of cell growth / RMTs methylate histone arginines / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / nervous system development / Replication of the SARS-CoV-2 genome / histone binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / DNA-binding transcription factor binding / amyloid fibril formation / transcription coactivator activity / molecular adaptor activity / protein stabilization / protein ubiquitination / transcription cis-regulatory region binding / hydrolase activity / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / intracellular membrane-bounded organelle / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / chromatin binding / positive regulation of cell population proliferation / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II
Similarity search - Function
BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / domain in helicases and associated with SANT domains / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2, ATP coupling domain ...BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / domain in helicases and associated with SANT domains / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2, ATP coupling domain / Snf2-ATP coupling, chromatin remodelling complex / Snf2-ATP coupling, chromatin remodelling complex / HSA domain / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Helicase/SANT-associated domain / HSA domain profile. / Elongin B / Elongin-C / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Helicase conserved C-terminal domain / Ubiquitin family / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin homologues / Ubiquitin-like domain / Bromodomain / Ubiquitin domain profile. / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Ubiquitin-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-IEI / von Hippel-Lindau disease tumor suppressor / Probable global transcription activator SNF2L2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.24 Å
AuthorsRoy, M.J. / Bader, G. / Farnaby, W. / Ciulli, A.
Funding support Austria, United Kingdom, 4items
OrganizationGrant numberCountry
Other private Austria
Wellcome Trust100476/Z/12/Z United Kingdom
Wellcome Trust094090/Z/10/Z United Kingdom
Austrian Research Promotion Agency871904 Austria
CitationJournal: 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
DepositionMar 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Probable global transcription activator SNF2L2
B: von Hippel-Lindau disease tumor suppressor
C: Elongin-C
D: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8445
Polymers55,8064
Non-polymers1,0381
Water1,15364
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance, gel filtration, isothermal titration calorimetry, SPR
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5700 Å2
ΔGint-42 kcal/mol
Surface area23370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.308, 86.808, 59.261
Angle α, β, γ (deg.)90.000, 98.900, 90.000
Int Tables number4
Space group name H-MP1211

-
Components

-
Protein , 4 types, 4 molecules ABCD

#1: Protein Probable global transcription activator SNF2L2 / ATP-dependent helicase SMARCA2 / BRG1-associated factor 190B / BAF190B / Protein brahma homolog / ...ATP-dependent helicase SMARCA2 / BRG1-associated factor 190B / BAF190B / Protein brahma homolog / hBRM / SNF2-alpha / SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2


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
#2: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


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 Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


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 Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


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 / (2~{S},4~{R})-~{N}-[[2-[3-[4-(4-bromanyl-7-cyclopentyl-5-oxidanylidene-benzimidazolo[1,2-a]quinazolin-9-yl)piperidin-1-yl]propoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide / (2S,4R)-N-(2-(3-(4-(4-bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[1,2-a]quinazolin-9- yl)piperidin-1-yl)propoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide


Mass: 1038.077 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H62BrFN8O6S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 64 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.15 Å3/Da / Density % sol: 42.9 %
Crystal growTemperature: 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

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 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

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.24-2.386.1120.8112.1521613365635360.7130.8996.7
2.38-2.546.380.6273.1821684340233990.8860.68599.9
2.54-2.756.570.4535.0720913318731830.9420.49499.9
2.75-3.016.7750.268.1720048296429590.9780.28299.8
3.01-3.366.880.14912.4418355266826680.9910.162100
3.36-3.886.5970.11317.0115555236223580.9920.12399.8
3.88-4.746.4460.08122.0712841199919920.9920.08999.6
4.74-6.686.2140.07723.029694156315600.9940.08499.8
6.68-48.546.0490.06825.5853538938850.9960.07499.1

-
Phasing

PhasingMethod: molecular replacement

-
Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5t35

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
RfactorNum. reflection% reflectionSelection details
Rfree0.232 1127 5 %RANDOM
Rwork0.189 ---
obs0.191 22540 98.7 %-
Displacement parametersBiso max: 144.31 Å2 / Biso mean: 52.75 Å2 / Biso min: 22.03 Å2
Baniso -1Baniso -2Baniso -3
1-8.3279 Å20 Å29.7494 Å2
2---6.7733 Å20 Å2
3----1.5546 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.24→48.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3600 0 70 64 3734
Biso mean--42.98 47.06 -
Num. residues----458
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1305SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes85HARMONIC2
X-RAY DIFFRACTIONt_gen_planes584HARMONIC5
X-RAY DIFFRACTIONt_it3757HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion495SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4209SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3757HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5110HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion3.2
X-RAY DIFFRACTIONt_other_torsion18.72
LS refinement shellResolution: 2.24→2.35 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.314 137 4.97 %
Rwork0.256 2619 -
all0.259 2756 -
obs--91.57 %
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)
15.6972-0.31721.40631.7593-0.94773.58420.16940.26710.094-0.0206-0.04740.1062-0.07780.0277-0.122-0.00480.05150.0859-0.17590.0802-0.0878-38.267314.8443-13.4752
25.37392.02540.68572.1950.44140.7907-0.16690.58610.1375-0.21010.1619-0.1161-0.0583-0.09440.005-0.0417-0.00910.0449-0.03510.0778-0.1703-9.24872.22254.2725
33.4644-0.93290.50422.22-0.81752.3647-0.03590.1004-0.05060.00150.0342-0.04470.06970.09320.00170.0327-0.0161-0.0041-0.1311-0.0097-0.051911.5056-6.69820.4532
42.3762-1.32051.09634.2366-2.86944.3592-0.1527-0.7047-0.35920.21320.65430.51420.007-0.5267-0.5015-0.08560.0680.0546-0.06760.103-0.14667.4229-11.987636.8492
50.57660.89870.21680.01910.83411.15480.072-0.2632-0.0303-0.1524-0.0585-0.021-0.26960.0718-0.0135-0.04860.00390.02280.02130.0840.0297-26.05538.8512-3.712
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-2-110 }A-2 - 110
2X-RAY DIFFRACTION2{ B|* }B61 - 209
3X-RAY DIFFRACTION3{ C|* }C16 - 112
4X-RAY DIFFRACTION4{ D|* }D1 - 104
5X-RAY DIFFRACTION5{ A|201 }A201

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more