5VBR

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRDT IN COMPLEX WITH Volasertib

PDB DOI: https://doi.org/10.2210/pdb5VBR/pdb

Classification: TRANSCRIPTION/INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2017-03-30 Released: 2018-04-04
Deposition Author(s): EMBER, S.W., ZHU, J.-Y., SCHONBRUNN, E.
Funding Organization(s): National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.201
R-Value Work: 0.155

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.

Karim, R.M., Bikowitz, M.J., Chan, A., Zhu, J.Y., Grassie, D., Becker, A., Berndt, N., Gunawan, S., Lawrence, N.J., Schonbrunn, E.

(2021) J Med Chem

PubMed: 34710325 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acs.jmedchem.1c01096
Primary Citation of Related Structures:
5V67, 5VBO, 5VBP, 5VBQ, 5VBR, 7BJY, 7K6G, 7K6H, 7KO0, 7L6D, 7L72, 7L73, 7L9G, 7L9J, 7L9K, 7L9L, 7LAH, 7LAI, 7LAJ, 7LAK, 7LAU, 7LAY, 7LAZ, 7LB4, 7LBT, 7LEJ, 7LEK, 7LEL, 7LEM

PubMed Abstract:
BRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially.

Organizational Affiliation

Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, United States.

Macromolecule Content

Total Structure Weight: 28.63 kDa
Atom Count: 2,196
Modelled Residue Count: 221
Deposited Residue Count: 226
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bromodomain testis-specific protein	A, B	113	Homo sapiens	Mutation(s): 0 Gene Names: BRDT
UniProt & NIH Common Fund Data Resources
Find proteins for Q58F21 (Homo sapiens) Explore Q58F21 Go to UniProtKB: Q58F21
PHAROS: Q58F21 GTEx: ENSG00000137948
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q58F21
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
IBI Query on IBI Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain K [auth B] MOL2 format, chain C [auth A] MOL2 format, chain K [auth B] mmCIF format, chain C [auth A] mmCIF format, chain K [auth B]	C [auth A], K [auth B]	N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide C₃₄ H₅₀ N₈ O₃ SXNJFOWDRLKDSF-STROYTFGSA-N		Interactions Focus chain C [auth A] Focus chain K [auth B] Interactions & Density Focus chain C [auth A] Focus chain K [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], L [auth B], M [auth B], N [auth B], O [auth B], P [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain L [auth B] Focus chain M [auth B] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain Q [auth B] MOL2 format, chain J [auth A] MOL2 format, chain Q [auth B] mmCIF format, chain J [auth A] mmCIF format, chain Q [auth B]	J [auth A], Q [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain J [auth A] Focus chain Q [auth B] Interactions & Density Focus chain J [auth A] Focus chain Q [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.201
R-Value Work: 0.155
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 65.45	α = 90
b = 31.05	β = 97.09
c = 69.8	γ = 90

Software Package:

Software Name	Purpose
XSCALE	data scaling
SERGUI	data collection
PHENIX	refinement
PDB_EXTRACT	data extraction
XDS	data reduction
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2018-04-04

Deposition Author(s):

EMBER, S.W.

ZHU, J.-Y.

SCHONBRUNN, E.

Funding Organization	Location	Grant Number
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)	United States	HD076542-01S1

Revision History (Full details and data files)

Version 1.0: 2018-04-04
Type: Initial release
Version 1.1: 2018-04-11
Changes: Data collection, Derived calculations, Structure summary
Version 1.2: 2019-12-11
Changes: Author supporting evidence, Derived calculations, Structure summary
Version 1.3: 2021-11-17
Changes: Database references
Version 1.4: 2023-10-04
Changes: Data collection, Refinement description