8SZU

Structure of Kdac1-Citarinostat complex from Acinetobacter baumannii

8SZU の概要

• エントリーDOI: 10.2210/pdb8szu/pdb
• 分子名称: Histone deacetylase domain-containing protein, Citarinostat, ZINC ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, metallohydrolase
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83038.91

構造登録者

Watson, P.R.,Christianson, D.W. (登録日: 2023-05-30, 公開日: 2023-09-06, 最終更新日: 2023-11-08)

主引用文献

Watson, P.R.,Christianson, D.W.
Structure and Function of Kdac1, a Class II Deacetylase from the Multidrug-Resistant Pathogen Acinetobacter baumannii .
Biochemistry, 62:2689-2699, 2023

PubMed Abstract: Proteomics studies indicate that 10% of proteins in the opportunistic pathogen are acetylated, suggesting that lysine acetyltransferases and deacetylases function to maintain and regulate a robust bacterial acetylome. As the first step in exploring these fascinating prokaryotic enzymes, we now report the preparation and characterization of the lysine deacetylase Kdac1. We show that Kdac1 catalyzes the deacetylation of free acetyllysine and acetyllysine tetrapeptide assay substrates, and we also report the X-ray crystal structures of unliganded Kdac1 as well as its complex with the hydroxamate inhibitor Citarinostat. Kdac1 is a tetramer in solution and in the crystal; the crystal structure reveals that the L1 loop functions to stabilize quaternary structure, forming inter-subunit hydrogen bonds and salt bridges around a central arginine residue (R30). Surprisingly, the L1 loop partially blocks entry to the active site, but it is sufficiently flexible to allow for the binding of two Citarinostat molecules in the active site. The L12 loop is also important for maintaining quaternary structure; here, a conserved arginine (R278) accepts hydrogen bonds from the backbone carbonyl groups of residues in an adjacent monomer. Structural comparisons with two other prokaryotic lysine deacetylases reveal conserved residues in the L1 and L12 loops that similarly support tetramer assembly. These studies provide a structural foundation for understanding enzymes that regulate protein function in bacteria through reversible lysine acetylation, serving as a first step in the exploration of these enzymes as possible targets for the development of new antibiotics.

PubMed: 37624144
DOI: 10.1021/acs.biochem.3c00288

実験手法

X-RAY DIFFRACTION (1.75 Å)