9EFJ

Irreversible Mcl-1/HIT2 Complex

これはPDB形式変換不可エントリーです。

9EFJ の概要

• エントリーDOI: 10.2210/pdb9efj/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, (1R)-N-{5-[(dihydroxy-lambda~4~-sulfanyl)oxy]pyridin-3-yl}-2,3-dihydro-1H-indene-1-carboxamide (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)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17771.20

構造登録者

Muzzarelli, K.M.,Assar, Z.,Udompholkul, P.,Pellecchia, M.,Baggio, C.,Prentiss, A.M. (登録日: 2024-11-20, 公開日: 2025-11-19, 最終更新日: 2025-12-10)

主引用文献

Alboreggia, G.,Muzzarelli, K.,Assar, Z.,Pellecchia, M.
A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1.
J.Med.Chem., 68:24305-24315, 2025

PubMed Abstract: Aryl-fluorosulfates are mild electrophiles that are very stable in biological media and in vivo and can efficiently react with the side chains of Lys, Tyr, or His residues, when properly juxtaposed by a high-affinity ligand. A more powerful approach to derive novel ligands would consist of starting from the covalent adduct and building the ligand off those initial interactions. While this strategy has been proven for Cys with molecular fragments containing Cys targeting electrophiles such as acrylamides, a corresponding strategy with fluorosulfates targeting His/Lys/Tyr residues has yet to be reported. We report here that a fragment library of aryl-fluorosulfates, when deployed with proper biophysical screening strategies, can identify initial covalent fragments. We report on novel strategies to enhance the success rate of such electrophile-based fragment screening for His/Lys/Tyr residues and to characterize the resulting hits. As an application, we report on novel covalent fragment hits targeting hMcl-1 His 224.

PubMed: 41223148
DOI: 10.1021/acs.jmedchem.5c02199

実験手法

X-RAY DIFFRACTION (1.82 Å)