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- PDB-7z76: Crystal structure of compound 10 in complex with the bromodomain ... -

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Entry
Database: PDB / ID: 7z76
TitleCrystal structure of compound 10 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 / regulation of cellular response to hypoxia / npBAF complex / nBAF complex / brahma complex / GBAF complex / RHOBTB3 ATPase cycle / nucleosome array spacer activity / negative regulation of receptor signaling pathway via JAK-STAT / regulation of G0 to G1 transition ...bBAF complex / regulation of cellular response to hypoxia / npBAF complex / nBAF complex / brahma complex / GBAF complex / RHOBTB3 ATPase cycle / nucleosome array spacer activity / negative regulation of receptor signaling pathway via JAK-STAT / regulation of G0 to G1 transition / target-directed miRNA degradation / transcription elongation factor activity / regulation of nucleotide-excision repair / VCB complex / intermediate filament cytoskeleton / elongin complex / Replication of the SARS-CoV-1 genome / SWI/SNF complex / regulation of mitotic metaphase/anaphase transition / Cul5-RING ubiquitin ligase complex / positive regulation of T cell differentiation / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / positive regulation of double-strand break repair / SUMOylation of ubiquitinylation proteins / spermatid development / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / positive regulation of stem cell population maintenance / 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 / ATP-dependent activity, acting on DNA / positive regulation of myoblast differentiation / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of signal transduction / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / protein serine/threonine kinase binding / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / helicase activity / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / negative regulation of cell growth / Inactivation of CSF3 (G-CSF) signaling / cell morphogenesis / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / 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 / nervous system development / Neddylation / microtubule cytoskeleton / regulation of gene expression / Replication of the SARS-CoV-2 genome / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / cellular response to hypoxia / histone binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / transcription coactivator activity / hydrolase activity / transcription cis-regulatory region binding / protein stabilization / protein ubiquitination / cilium / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / negative regulation of DNA-templated transcription / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / ubiquitin protein ligase binding / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process
Similarity search - Function
BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2-ATP coupling, chromatin remodelling complex / Snf2, ATP coupling domain ...BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2-ATP coupling, chromatin remodelling complex / Snf2, ATP coupling domain / Snf2-ATP coupling, chromatin remodelling complex / 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 / domain in helicases and associated with SANT domains / HSA domain / Helicase/SANT-associated domain / HSA domain profile. / Elongin-C / Elongin B / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / SKP1/BTB/POZ domain superfamily / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Helicase conserved C-terminal domain / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin-like (UB roll) / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / 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 / Roll / P-loop containing nucleoside triphosphate hydrolase / Alpha Beta
Similarity search - Domain/homology
Chem-IFJ / IODIDE ION / 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: 1.32 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)57,77112
Polymers55,8064
Non-polymers1,9668
Water12,106672
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7350 Å2
ΔGint-41 kcal/mol
Surface area22880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.469, 101.395, 69.131
Angle α, β, γ (deg.)90.000, 105.560, 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 , 3 types, 680 molecules

#5: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#6: Chemical ChemComp-IFJ / (2~{S},4~{R})-~{N}-[(1~{R})-2-[(2~{R})-1-[4-(4-bromanyl-7-cyclopentyl-5-oxidanylidene-benzimidazolo[1,2-a]quinazolin-9-yl)piperidin-1-yl]propan-2-yl]oxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2~{S})-2-[[1-(dimethylamino)cyclopropyl]carbonylamino]-3,3-dimethyl-butanoyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 1077.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C56H70BrN9O6S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 672 / 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: 2.87 Å3/Da / Density % sol: 57.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 14.5 % PEG 3350, 0.1 M BIS-TRIS propane pH 5.8, 100 mM sodium iodide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 1.32→66.59 Å / Num. obs: 104311 / % possible obs: 92 % / Redundancy: 4.5 % / CC1/2: 0.999 / Net I/σ(I): 12.1
Reflection shellResolution: 1.32→1.45 Å / Num. unique obs: 5216 / CC1/2: 0.51

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Processing

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

5t35

4qy4


Resolution: 1.32→33.96 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.059 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.063 / SU Rfree Blow DPI: 0.064 / SU Rfree Cruickshank DPI: 0.061
RfactorNum. reflection% reflectionSelection details
Rfree0.202 5233 5.02 %RANDOM
Rwork0.178 ---
obs0.179 104311 71.3 %-
Displacement parametersBiso max: 108.8 Å2 / Biso mean: 27.12 Å2 / Biso min: 10.27 Å2
Baniso -1Baniso -2Baniso -3
1-0.4077 Å20 Å2-0.2302 Å2
2--0.3925 Å20 Å2
3----0.8003 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: final / Resolution: 1.32→33.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3632 0 80 672 4384
Biso mean--16.53 39.43 -
Num. residues----449
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1363SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes678HARMONIC5
X-RAY DIFFRACTIONt_it3805HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion490SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies2HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4910SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3805HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5168HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion15.19
LS refinement shellResolution: 1.32→1.41 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2721 112 5.37 %
Rwork0.2336 1975 -
all0.2357 2087 -
obs--8.69 %
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)
10.69520.32850.1821.8598-0.49571.70550.0285-0.1058-0.06030.1381-0.0460.07610.1315-0.02920.0175-0.0126-0.0090.0133-0.05590.0112-0.05662.4747-8.949312.197
21.0338-0.0430.22910.6779-0.64041.8541-0.01590.0192-0.0875-0.0656-0.0603-0.0640.15160.17830.0762-0.01810.01360.0157-0.0250.0117-0.03987.0096-5.2344-5.0671
31.19710.13460.41130.2938-0.03640.41440.00330.067-0.0675-0.04810.0048-0.00130.0131-0.0317-0.0081-0.02180.0081-0.0001-0.00320.0001-0.0264-13.61993.5455-21.593
40.6721-0.1896-0.45490.8205-0.16221.54780.11990.15830.0107-0.1635-0.01660.123-0.3147-0.1182-0.10330.02550.0221-0.0242-0.03580.0162-0.0739-32.919916.3392-45.4071
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 104
2X-RAY DIFFRACTION2{ B|* }B17 - 112
3X-RAY DIFFRACTION3{ C|* }C60 - 202
4X-RAY DIFFRACTION4{ D|* }D1377 - 1489

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