7K6G

Crystal structure of the first bromodomain (BD1) of human BRD4 bound to ERK5-IN-1

PDB DOI: https://doi.org/10.2210/pdb7K6G/pdb

Classification: GENE REGULATION
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2020-09-20 Released: 2021-09-29
Deposition Author(s): Karim, M.R., Zhu, J.Y., Schonbrunn, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.70 Å
R-Value Free: 0.204
R-Value Work: 0.171
R-Value Observed: 0.172

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 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 64: 15772-15786

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: 32.94 kDa
Atom Count: 2,652
Modelled Residue Count: 254
Deposited Residue Count: 254
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-containing protein 4	A, B	127	Homo sapiens	Mutation(s): 0 Gene Names: BRD4, HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens) Explore O60885 Go to UniProtKB: O60885
PHAROS: O60885 GTEx: ENSG00000141867
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O60885
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
VYJ (Subject of Investigation/LOI) Query on VYJ Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B]	C [auth A], D [auth A], E [auth A], H [auth B]	11-cyclopentyl-2-({2-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]phenyl}amino)-5-methyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one C₃₆ H₄₆ N₈ O₃ XVBGRTMNFNMINE-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain H [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain I [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain I [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain I [auth B]	F [auth A], G [auth A], I [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain I [auth B]