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- PDB-5s9o: CRYSTAL STRUCTURE OF THE HUMAN BRD2 BD1 BROMODOMAIN IN COMPLEX WI... -

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Basic information

Entry
Database: PDB / ID: 5s9o
TitleCRYSTAL STRUCTURE OF THE HUMAN BRD2 BD1 BROMODOMAIN IN COMPLEX WITH 9-(cyclopropylmethyl)-7-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-9H-carbazole-1-carboxamide
ComponentsBromodomain-containing protein 2BRD2
KeywordsCELL CYCLE / HELICAL BUNDLE / ACETYL-LYSINE RECOGNITION / ACETYLATED HISTONE H4 / NUCLEUS / TRANSCRIPTION-TRANSCRIPTION INHIBITOR COMPLEX
Function / homology
Function and homology information


chromatin organization
Similarity search - Function
NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. ...NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-YW1 / Bromodomain-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.49 Å
AuthorsSheriff, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
Authors: Gavai, A.V. / Norris, D. / Delucca, G. / Tortolani, D. / Tokarski, J.S. / Dodd, D. / O'Malley, D. / Zhao, Y. / Quesnelle, C. / Gill, P. / Vaccaro, W. / Huynh, T. / Ahuja, V. / Han, W.C. / ...Authors: Gavai, A.V. / Norris, D. / Delucca, G. / Tortolani, D. / Tokarski, J.S. / Dodd, D. / O'Malley, D. / Zhao, Y. / Quesnelle, C. / Gill, P. / Vaccaro, W. / Huynh, T. / Ahuja, V. / Han, W.C. / Mussari, C. / Harikrishnan, L. / Kamau, M. / Poss, M. / Sheriff, S. / Yan, C. / Marsilio, F. / Menard, K. / Wen, M.L. / Rampulla, R. / Wu, D.R. / Li, J. / Zhang, H. / Li, P. / Sun, D. / Yip, H. / Traeger, S.C. / Zhang, Y. / Mathur, A. / Zhang, H. / Huang, C. / Yang, Z. / Ranasinghe, A. / Everlof, G. / Raghavan, N. / Tye, C.K. / Wee, S. / Hunt, J.T. / Vite, G. / Westhouse, R. / Lee, F.Y.
History
DepositionApr 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 2
B: Bromodomain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,52513
Polymers33,9652
Non-polymers1,56011
Water1,71195
1
A: Bromodomain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8568
Polymers16,9831
Non-polymers8737
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area350 Å2
ΔGint5 kcal/mol
Surface area7950 Å2
MethodPISA
2
B: Bromodomain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,6695
Polymers16,9831
Non-polymers6874
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area680 Å2
ΔGint9 kcal/mol
Surface area7550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)134.270, 134.270, 134.270
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23

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Components

#1: Protein Bromodomain-containing protein 2 / BRD2


Mass: 16982.607 Da / Num. of mol.: 2 / Fragment: RESIDUES 73-194
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD2 / Plasmid: PET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: A0A140T9E9
#2: Chemical ChemComp-YW1 / 9-(cyclopropylmethyl)-7-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-9H-carbazole-1-carboxamide


Mass: 500.589 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H32N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
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: 2.97 Å3/Da / Density % sol: 58.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 200 mM Ammonium Citrate Dibasic, 16%(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 2.49→35.89 Å / Num. obs: 14315 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 19.7 % / Biso Wilson estimate: 50.84 Å2 / Rsym value: 0.115 / Net I/σ(I): 22.6
Reflection shellResolution: 2.49→2.62 Å / Redundancy: 20.7 % / Mean I/σ(I) obs: 6.5 / Rsym value: 0.553 / Rejects: 0 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
SCALAdata scaling
PHASERphasing
BUSTER2.11.4refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3AQA

3aqa


Resolution: 2.49→35.89 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.278 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.276 / SU Rfree Blow DPI: 0.192 / SU Rfree Cruickshank DPI: 0.193
RfactorNum. reflection% reflectionSelection details
Rfree0.2003 730 5.11 %RANDOM
Rwork0.1775 ---
obs0.1786 14277 100 %-
Displacement parametersBiso max: 143.66 Å2 / Biso mean: 41.01 Å2 / Biso min: 19.99 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.252 Å
Refinement stepCycle: final / Resolution: 2.49→35.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1949 0 110 95 2154
Biso mean--43.16 42.69 -
Num. residues----235
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d754SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes364HARMONIC5
X-RAY DIFFRACTIONt_it2175HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion257SEMIHARMONIC5
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_contact2434SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2175HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2993HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion19.08
LS refinement shellResolution: 2.49→2.69 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2278 176 6.03 %
Rwork0.1815 2742 -
all0.1843 2918 -
obs--100 %

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