PDBsum entry 5o5f

DNA binding protein

PDB id: 5o5f

Contents

Protein chain

113 a.a.

Ligands

9LT

NO3 ×2

Waters ×223

PDB id:

5o5f

Name:

DNA binding protein

Title:

Crystal structure of the human brpf1 bromodomain in complex with bz038

Structure:

Peregrin. Chain: a. Synonym: bromodomain and phd finger-containing protein 1,protein br140. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brpf1, br140. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.30Å R-factor: 0.176 R-free: 0.188

Authors:

J.Zhu,A.Caflisch

Key ref:

J.Zhu et al. (2018). Structure-based discovery of selective BRPF1 bromodomain inhibitors. Eur J Med Chem, 155, 337-352. PubMed id: 29902720 DOI: 10.1016/j.ejmech.2018.05.037

Date:

01-Jun-17 Release date: 13-Jun-18

Protein chain

P55201  (BRPF1_HUMAN) -  Peregrin from Homo sapiens

Seq: 1214 a.a.

Struc: 113 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.ejmech.2018.05.037

Eur J Med Chem 155:337-352 (2018)

PubMed id: 29902720

Structure-based discovery of selective BRPF1 bromodomain inhibitors.

J.Zhu, C.Zhou, A.Caflisch.

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_D = 3 μM), and the 2,4-dimethyl-oxazole derivative 42 (K_D = 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.