6EKQ

Crystal structure of the human BRPF1 bromodomain complexed with BZ054 in space group C2

Summary for 6EKQ

• Entry DOI: 10.2210/pdb6ekq/pdb
• Descriptor: Peregrin, ~{N}-[4-[[(3~{S},5~{R})-3,5-dimethylpiperidin-1-yl]methyl]-1,3-thiazol-2-yl]-2,4-dimethyl-1,3-oxazole-5-carboxamide, NITRATE ION, ... (4 entities in total)
• Functional Keywords: bromodomain and phd finger-containing protein 1(brpf1), monocytic leukemia zinc-finger (moz), inhibitor, transcription, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28228.33

Authors

Zhu, J.,Caflisch, A. (deposition date: 2017-09-26, release date: 2018-06-27, Last modification date: 2024-01-17)

Primary citation

Zhu, J.,Zhou, C.,Caflisch, A.
Structure-based discovery of selective BRPF1 bromodomain inhibitors.
Eur J Med Chem, 155:337-352, 2018

PubMed Abstract: Bromodomain and plant homeodomain (PHD) finger containing protein 1 (BRPF1) is a member of subfamily IV of the human bromodomains. Experimental evidence suggests that BRPF1 is involved in leukemia. In a previous high-throughput docking campaign we identified several chemotypes targeting the BRPF1 bromodomain. Here, pharmacophore searches using the binding modes of two of these chemotypes resulted in two new series of ligands of the BRPF1 bromodomain. The 2,3-dioxo-quinoxaline 21 exhibits a 2-μM affinity for the BRPF1 bromodomain in two different competition binding assays, and more than 100-fold selectivity for BRPF1 against other members of subfamily IV and representatives of other subfamilies. Cellular activity is confirmed by a viability assay in a leukemia cell line. Isothermal titration calorimetry measurements reveal enthalpy-driven binding for compounds 21, 26 (K = 3 μM), and the 2,4-dimethyl-oxazole derivative 42 (K = 10 μM). Multiple molecular dynamics simulations and a dozen co-crystal structures at high resolution provide useful information for further optimization of affinity for the BRPF1 bromodomain.

PubMed: 29902720
DOI: 10.1016/j.ejmech.2018.05.037

Experimental method

X-RAY DIFFRACTION (1.65 Å)