6WSJ

Crystal Structure of Danio rerio histone deacetylase 6 catalytic domain 2 complexed with cyclopeptide des4.3.1

6WSJ の概要

• エントリーDOI: 10.2210/pdb6wsj/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002383
• 分子名称: Hdac6 protein, cyclopeptide des4.3.1, ZINC ION, ... (6 entities in total)
• 機能のキーワード: hydrolase, histone deacetylase, inhibitor, metallohydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Danio rerio (Zebrafish); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41550.44

構造登録者

Watson, P.R.,Christianson, D.W. (登録日: 2020-05-01, 公開日: 2021-04-28, 最終更新日: 2023-11-15)

主引用文献

Hosseinzadeh, P.,Watson, P.R.,Craven, T.W.,Li, X.,Rettie, S.,Pardo-Avila, F.,Bera, A.K.,Mulligan, V.K.,Lu, P.,Ford, A.S.,Weitzner, B.D.,Stewart, L.J.,Moyer, A.P.,Di Piazza, M.,Whalen, J.G.,Greisen, P.J.,Christianson, D.W.,Baker, D.
Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.
Nat Commun, 12:3384-3384, 2021

PubMed Abstract: Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain.

PubMed: 34099674
DOI: 10.1038/s41467-021-23609-8

実験手法

X-RAY DIFFRACTION (1.7 Å)