6UO2

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) complexed with Trichostatin A

6UO2 の概要

• エントリーDOI: 10.2210/pdb6uo2/pdb
• 分子名称: HDAC6, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• 機能のキーワード: histone deacetylase, hydrolase
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81481.13

構造登録者

Osko, J.D.,Christianson, D.W. (登録日: 2019-10-14, 公開日: 2019-12-04, 最終更新日: 2023-10-11)

主引用文献

Osko, J.D.,Christianson, D.W.
Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6.
Biochemistry, 58:4912-4924, 2019

PubMed Abstract: Histone deacetylase 6 (HDAC6) is emerging as a target for inhibition in therapeutic strategies aimed at treating cancer, neurodegenerative disease, and other disorders. Among the metal-dependent HDAC isozymes, HDAC6 is unique in that it contains two catalytic domains, CD1 and CD2. CD2 is a tubulin deacetylase and a tau deacetylase, and the development of HDAC6-selective inhibitors has focused exclusively on this domain. In contrast, there is a dearth of structural and functional information regarding CD1, which exhibits much narrower substrate specificity in comparison with CD2. As the first step in addressing the CD1 information gap, we now present X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1. These structures broaden our understanding of molecular features that are important for catalysis and inhibitor binding. The active site of HDAC6 CD1 is wider than that of CD2, which is unexpected in view of the narrow substrate specificity of CD1. Amino acid substitutions between HDAC6 CD1 and CD2, as well as conformational differences in conserved residues, define striking differences in active site contours. Catalytic activity measurements with HDAC6 CD1 confirm the preference for peptide substrates containing C-terminal acetyllysine residues. However, these measurements also show that CD1 exhibits weak activity for peptide substrates bearing certain small amino acids on the carboxyl side of the scissile acetyllysine residue. Taken together, these results establish a foundation for understanding the structural basis of HDAC6 CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC6 CD1-selective inhibitors.

PubMed: 31755702
DOI: 10.1021/acs.biochem.9b00934

実験手法

X-RAY DIFFRACTION (1.65002315533 Å)