Issue 25, 2021

Structural variation of protein–ligand complexes of the first bromodomain of BRD4

Abstract

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) family, plays a key role in several diseases, especially cancers. With increased interest in BRD4 as a therapeutic target, many X-ray crystal structures of the protein in complex with small molecule inhibitors are publicly available over the recent decade. In this study, we use this structural information to investigate the conformations of the first bromodomain (BD1) of BRD4. Structural alignment of 297 BRD4-BD1 complexes shows a high level of similarity between the structures of BRD4-BD1, regardless of the bound ligand. We employ WONKA, a tool for detailed analyses of protein binding sites, to compare the active site of over 100 of these crystal structures. The positions of key binding site residues show a high level of conformational similarity, with the exception of Trp81. A focused analysis on the highly conserved water network in the binding site of BRD4-BD1 is performed to identify the positions of these water molecules across the crystal structures. The importance of the water network is illustrated using molecular docking and absolute free energy perturbation simulations. 82% of the ligand poses were better predicted when including water molecules as part of the receptor. Our analysis provides guidance for the design of new BRD4-BD1 inhibitors and the selection of the best structure of BRD4-BD1 to use in structure-based drug design, an important approach for faster and more cost-efficient lead discovery.

Graphical abstract: Structural variation of protein–ligand complexes of the first bromodomain of BRD4

Supplementary files

Article information

Article type
Paper
Submitted
05 avr. 2021
Accepted
03 juin 2021
First published
04 juin 2021
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2021,19, 5632-5641

Structural variation of protein–ligand complexes of the first bromodomain of BRD4

E. E. Guest, S. D. Pickett and J. D. Hirst, Org. Biomol. Chem., 2021, 19, 5632 DOI: 10.1039/D1OB00658D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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