6WHN

Histone deacetylases complex with peptide macrocycles

6WHN の概要

• エントリーDOI: 10.2210/pdb6whn/pdb
• 分子名称: Histone deacetylase 2, U2M-ASN-PRO-LYS-GLN-DLY-TRP-GLY peptide macrocycle, ZINC ION, ... (9 entities in total)
• 機能のキーワード: anchor extension, de novo design macrocycles, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 137322.34

構造登録者

Bera, A.K.,Hosseinzadeh, P.,Watson, P.,Baker, D. (登録日: 2020-04-08, 公開日: 2021-04-21, 最終更新日: 2024-10-30)

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 (1.54 Å)