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- PDB-6hm0: Crystal structure of human BRD9 bromodomain in complex with a PROTAC -

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Basic information

Entry
Database: PDB / ID: 6hm0
TitleCrystal structure of human BRD9 bromodomain in complex with a PROTAC
ComponentsBromodomain-containing protein 9
KeywordsTRANSCRIPTION / PROTAC / LYSINE-ACETYLATED HISTONE BINDING / CHROMATIN REGULATOR
Function / homology
Function and homology information


GBAF complex / SWI/SNF complex / positive regulation of stem cell population maintenance / negative regulation of cell differentiation / lysine-acetylated histone binding / nucleic acid binding / chromatin remodeling / chromatin / positive regulation of cell population proliferation / regulation of transcription by RNA polymerase II ...GBAF complex / SWI/SNF complex / positive regulation of stem cell population maintenance / negative regulation of cell differentiation / lysine-acetylated histone binding / nucleic acid binding / chromatin remodeling / chromatin / positive regulation of cell population proliferation / regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Protein of unknown function DUF3512 / Domain of unknown function (DUF3512) / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-GBW / Bromodomain-containing protein 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsHughes, S.J. / Zoppi, V. / Ciulli, A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2019
Title: Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel-Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7.
Authors: Zoppi, V. / Hughes, S.J. / Maniaci, C. / Testa, A. / Gmaschitz, T. / Wieshofer, C. / Koegl, M. / Riching, K.M. / Daniels, D.L. / Spallarossa, A. / Ciulli, A.
History
DepositionSep 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 9
B: Bromodomain-containing protein 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,4064
Polymers28,5002
Non-polymers1,9062
Water1,22568
1
A: Bromodomain-containing protein 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2032
Polymers14,2501
Non-polymers9531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2032
Polymers14,2501
Non-polymers9531
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.840, 59.820, 60.340
Angle α, β, γ (deg.)90.000, 108.750, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: MET / End label comp-ID: MET / Refine code: 0 / Auth seq-ID: 22 - 133 / Label seq-ID: 11 - 122

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Bromodomain-containing protein 9 / Rhabdomyosarcoma antigen MU-RMS-40.8


Mass: 14249.763 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD9, UNQ3040/PRO9856 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9H8M2
#2: Chemical ChemComp-GBW / (2~{S},4~{S})-1-[(2~{S})-2-[2-[2-[2-[4-[[2,6-dimethoxy-4-(2-methyl-1-oxidanylidene-2,7-naphthyridin-4-yl)phenyl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 953.156 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C50H64N8O9S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O

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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: 2.33 Å3/Da / Density % sol: 47.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 24% PEG 3350 0.2 M NH4F

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96862 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96862 Å / Relative weight: 1
ReflectionResolution: 2.4→41.3 Å / Num. obs: 10196 / % possible obs: 98.5 % / Redundancy: 4.2 % / CC1/2: 0.99 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.046 / Rrim(I) all: 0.096 / Net I/σ(I): 18.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.4-2.494.30.15710660.980.0840.17899.9
8.98-41.323.80.0522060.9950.0290.0695.3

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I40

5i40


Resolution: 2.4→41.3 Å / Cor.coef. Fo:Fc: 0.904 / Cor.coef. Fo:Fc free: 0.857 / SU B: 13.402 / SU ML: 0.173 / SU R Cruickshank DPI: 0.5559 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.556 / ESU R Free: 0.278
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2507 556 5.5 %RANDOM
Rwork0.2158 ---
obs0.2177 9627 98.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 53.38 Å2 / Biso mean: 22.469 Å2 / Biso min: 4.17 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å2-0 Å2-0.5 Å2
2--2.39 Å2-0 Å2
3----0.95 Å2
Refinement stepCycle: final / Resolution: 2.4→41.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1826 0 66 68 1960
Biso mean--21.62 23.39 -
Num. residues----224
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0141942
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171826
X-RAY DIFFRACTIONr_angle_refined_deg1.2021.7142606
X-RAY DIFFRACTIONr_angle_other_deg0.821.6834272
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4225222
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.82221.77890
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.91315364
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0331510
X-RAY DIFFRACTIONr_chiral_restr0.0550.2240
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022066
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02368
Refine LS restraints NCS

Ens-ID: 1 / Number: 3516 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.249 53 -
Rwork0.186 709 -
all-762 -
obs--99.74 %
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)
13.04350.44611.78531.0502-0.31185.9521-0.0179-0.15750.13730.1745-0.06490.0264-0.14240.08040.08280.0572-0.00940.03530.0149-0.00990.058218.07420.74234.0216
22.8642-0.3642-2.16391.10070.66856.1521-0.02470.3540.0918-0.1745-0.0016-0.0391-0.0553-0.15420.02630.0677-0.0206-0.03670.05190.01590.084637.46214.625-19.1708
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A22 - 133
2X-RAY DIFFRACTION2B22 - 133

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