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Structural Variation of BRD4-BD1 Complexes

preprint
submitted on 02.04.2021, 12:14 and posted on 05.04.2021, 05:45 by Ellen Guest, Stephen Pickett, Jonathan Hirst
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, over 300 X-ray crystal structures of the protein in complex with small molecule inhibitors
have become 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 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 crystal structures,
with a focus on the highly conserved network of water molecules, which line the binding pocket of BRD4-BD1.
The analysis presented in this work helps guide 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.

Funding

Accelerated Discovery and Development of New Medicines: Prosperity Partnership for a Healthier Nation

Engineering and Physical Sciences Research Council

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Industrial CASE Account - University of Nottingham 2017

Engineering and Physical Sciences Research Council

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Royal Academy of Engineering Chairs in Emerging Technologies

History

Email Address of Submitting Author

jonathan.hirst@nottingham.ac.uk

Institution

University of Nottingham

Country

United Kingdom

ORCID For Submitting Author

0000-0002-2726-0983

Declaration of Conflict of Interest

None

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