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- PDB-7z77: Crystal structure of compound 6 in complex with the bromodomain o... -

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Entry
Database: PDB / ID: 7z77
TitleCrystal structure of compound 6 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 / PROTAC / Complex / Bromodomain
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 / regulation of mitotic metaphase/anaphase transition / ATP-dependent chromatin remodeler activity / Replication of the SARS-CoV-1 genome / SWI/SNF complex / positive regulation of double-strand break repair / Cul5-RING ubiquitin ligase complex / 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 / negative regulation of transcription elongation by RNA polymerase II / 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 / spermatid development / 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 / helicase activity / transcription corepressor binding / transcription elongation by RNA polymerase II / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Vif-mediated degradation of APOBEC3G / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / negative regulation of cell growth / 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 / protein-macromolecule adaptor activity / nervous system development / Neddylation / Replication of the SARS-CoV-2 genome / 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 / protein stabilization / hydrolase activity / transcription cis-regulatory region binding / protein ubiquitination / 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 / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum
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 / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin family / Bromodomain / Ubiquitin homologues / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin domain profile. / helicase superfamily c-terminal domain / Ubiquitin-like 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-IFF / 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 / Resolution: 1.97 Å
AuthorsBader, G. / Boettcher, J. / Wolkerstorfer, B.
Funding support Austria, 1items
OrganizationGrant numberCountry
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 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)56,8285
Polymers55,8064
Non-polymers1,0221
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5790 Å2
ΔGint-37 kcal/mol
Surface area24130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.903, 63.707, 91.956
Angle α, β, γ (deg.)90.000, 101.320, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 4 types, 4 molecules ABCD

#1: 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 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#2: 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 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#3: 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 / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#4: 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 / Production host: Escherichia coli (E. coli)
References: UniProt: P51531, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement

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Non-polymers , 2 types, 101 molecules

#5: Chemical ChemComp-IFF / (2~{S},4~{R})-~{N}-[(1~{S})-4-[4-(4-bromanyl-7-cyclopentyl-5-oxidanylidene-benzimidazolo[1,2-a]quinazolin-9-yl)piperidin-1-yl]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]butyl]-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 1022.077 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H62BrFN8O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 2.52 Å3/Da / Density % sol: 51.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20 % PEG 3350, 0.1 M BIS_TRIS propane pH 7.5, 200 mM sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 4, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→90.17 Å / Num. obs: 29493 / % possible obs: 87.7 % / Redundancy: 5 % / CC1/2: 0.998 / Net I/σ(I): 12.3
Reflection shellResolution: 1.974→2.231 Å / Num. unique obs: 1176 / CC1/2: 0.487

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISO2.2.19data scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5T35, 4QY4

5t35

4qy4


Resolution: 1.97→30.06 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.922 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.331 / SU Rfree Blow DPI: 0.232
RfactorNum. reflection% reflectionSelection details
Rfree0.251 1194 5.08 %RANDOM
Rwork0.213 ---
obs0.215 23493 59.7 %-
Displacement parametersBiso max: 169.26 Å2 / Biso mean: 55.34 Å2 / Biso min: 24.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.9355 Å20 Å2-0.9494 Å2
2---0.1503 Å20 Å2
3----0.7852 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 1.97→30.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3706 0 69 100 3875
Biso mean--46.98 51.49 -
Num. residues----457
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1702SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1167HARMONIC5
X-RAY DIFFRACTIONt_it7669HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion497SEMIHARMONIC5
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_contact7982SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7669HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg13923HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion17.52
LS refinement shellResolution: 1.97→2.16 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2634 18 3.83 %
Rwork0.2363 452 -
all0.2372 470 -
obs--5.07 %
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)
10.2585-0.43910.50610.6028-0.25380.26910.00130.00990.014-0.0216-0.0015-0.0157-0.0183-0.00520.00020.00630.053-0.036-0.0126-0.0227-0.01599.127223.295525.4552
20.5543-0.6954-0.01650.67550.20960.3074-0.002-0.0132-0.00880.01670.0002-0.0014-0.0056-0.01130.0018-0.02470.0092-0.0052-0.0061-0.03640.018214.78210.200336.0369
30.4408-0.1095-0.17050.8080.66870.9955-0.0181-0.02650.017-0.0198-0.0031-0.01470.07640.00840.02120.00460.03980.0284-0.0319-0.0006-0.034625.8678-12.737424.9336
40.2026-0.62790.13820.5805-0.22711.4535-0.00410.00680.01090.0179-0.002-0.003-0.00480.02210.0061-0.00730.053-0.00520.02130.029-0.073740.5365-37.206-0.3322
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 104
2X-RAY DIFFRACTION2{ B|* }B16 - 112
3X-RAY DIFFRACTION3{ C|* }C60 - 210
4X-RAY DIFFRACTION4{ D|* }D1376 - 1490

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