7LTG

STRUCTURE OF HUMAN HDAC2 IN COMPLEX WITH APICIDIN

7LTG の概要

• エントリーDOI: 10.2210/pdb7ltg/pdb
• 分子名称: Histone deacetylase 2, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: histone deacetylase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 132609.25

構造登録者

Klein, D.J.,Beshore, D.C. (登録日: 2021-02-19, 公開日: 2021-05-05, 最終更新日: 2024-03-06)

主引用文献

Beshore, D.C.,Adam, G.C.,Barnard, R.J.O.,Burlein, C.,Gallicchio, S.N.,Holloway, M.K.,Krosky, D.,Lemaire, W.,Myers, R.W.,Patel, S.,Plotkin, M.A.,Powell, D.A.,Rada, V.,Cox, C.D.,Coleman, P.J.,Klein, D.J.,Wolkenberg, S.E.
Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.
Acs Med.Chem.Lett., 12:540-547, 2021

PubMed Abstract: A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

PubMed: 33854701
DOI: 10.1021/acsmedchemlett.1c00074

実験手法

X-RAY DIFFRACTION (1.8 Å)