9CKN

Histidine-covalent alpha-helical peptide (compound 6) targeting hMcl-1

9CKN の概要

• エントリーDOI: 10.2210/pdb9ckn/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Helical Peptide (3 entities in total)
• 機能のキーワード: histidine-covalent stapled alpha-helical peptides, apoptosis
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 38894.28

構造登録者

Muzzarelli, K.M.,Assar, Z.,Alboreggia, G.,Pellecchia, M. (登録日: 2024-07-09, 公開日: 2024-11-27, 最終更新日: 2024-12-11)

主引用文献

Alboreggia, G.,Udompholkul, P.,Atienza, E.L.,Muzzarelli, K.,Assar, Z.,Pellecchia, M.
Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics.
J.Med.Chem., 67:20214-20223, 2024

PubMed Abstract: Covalent drugs provide pharmacodynamic and pharmacokinetic advantages over reversible agents. However, covalent strategies have been developed mostly to target cysteine (Cys) residues, which are rarely found in binding sites. Among other nucleophilic residues that could be in principle used for the design of covalent drugs, histidine (His) has not been given proper attention despite being in principle an attractive residue to pursue but underexplored. Aryl fluorosulfates, a mild electrophile that is very stable in biological media, have been recently identified as possible electrophiles to react with the side chains of Lys; however, limited studies are available on aryl fluorosulfates' ability to target His residues. We demonstrate that proper incorporation of an aryl fluorosulfate juxtaposing the electrophile with a His residue can be used to afford rapid optimizations of His-covalent agents. As an application, we report on His-covalent BH3 mimetics targeting His224 of Mcl-1.

PubMed: 39532346
DOI: 10.1021/acs.jmedchem.4c01541

実験手法

X-RAY DIFFRACTION (1.5 Å)