8BPT

Crystal structure of the second bromodomain of BRD5 from Leishmania donovani

Summary for 8BPT

• Entry DOI: 10.2210/pdb8bpt/pdb
• Descriptor: Bromo domain-containing protein (2 entities in total)
• Functional Keywords: leishmaniasis, general transcription, lysine acetylation, transcription
• Biological source: Leishmania donovani BPK282A1
• Total number of polymer chains: 2
• Total formula weight: 31659.94

Authors

Wilkinson, A.J.,Dodson, E.J.,Jones, N.G.,Borgia, J. (deposition date: 2022-11-17, release date: 2023-09-27, Last modification date: 2023-11-22)

Primary citation

Russell, C.N.,Carter, J.L.,Borgia, J.M.,Bush, J.,Calderon, F.,Gabarro, R.,Conway, S.J.,Mottram, J.C.,Wilkinson, A.J.,Jones, N.G.
Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery.
Acs Infect Dis., 9:2340-2357, 2023

PubMed Abstract: Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus . Current chemotherapies are severely limited, and the need for new antileishmanials is of pressing international importance. Bromodomains are epigenetic reader domains that have shown promising therapeutic potential for cancer therapy and may also present an attractive target to treat parasitic diseases. Here, we investigate bromodomain factor 5 (BDF5) as a target for antileishmanial drug discovery. BDF5 contains a pair of bromodomains (BD5.1 and BD5.2) in an N-terminal tandem repeat. We purified recombinant bromodomains of BDF5 and determined the structure of BD5.2 by X-ray crystallography. Using a histone peptide microarray and fluorescence polarization assay, we identified binding interactions of BDF5 bromodomains with acetylated peptides derived from histones H2B and H4. In orthogonal biophysical assays including thermal shift assays, fluorescence polarization, and NMR, we showed that BDF5 bromodomains bind to human bromodomain inhibitors SGC-CBP30, bromosporine, and I-BRD9; moreover, SGC-CBP30 exhibited activity against promastigotes in cell viability assays. These findings exemplify the potential BDF5 holds as a possible drug target in and provide a foundation for the future development of optimized antileishmanial compounds targeting this epigenetic reader protein.

PubMed: 37906637
DOI: 10.1021/acsinfecdis.3c00431

Experimental method

X-RAY DIFFRACTION (1.6 Å)