5D1U

Anthrax toxin lethal factor with hydroxamic acid inhibitor

5D1U の概要

• エントリーDOI: 10.2210/pdb5d1u/pdb
• 関連するPDBエントリー: 1YQY 4PKQ 4PKR 4PKS 4PKT 4PKU 4PKV 4PKW
• 分子名称: Lethal factor, N~2~-(6-aminohexyl)-N~2~-[(4-fluoro-3-methylphenyl)sulfonyl]-N-hydroxy-D-alaninamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: anthrax toxin, lethal factor, metalloproteinase, metalloprotease, structural dynamics, ligand-induced conformational change, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Bacillus anthracis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60876.92

構造登録者

Maize, K.M.,Finzel, B.C. (登録日: 2015-08-04, 公開日: 2015-11-11, 最終更新日: 2023-09-27)

主引用文献

Kurbanov, E.K.,Chiu, T.L.,Solberg, J.,Francis, S.,Maize, K.M.,Fernandez, J.,Johnson, R.L.,Hawkinson, J.E.,Walters, M.A.,Finzel, B.C.,Amin, E.A.
Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates.
J.Med.Chem., 58:8723-8733, 2015

PubMed Abstract: The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding.

PubMed: 26492514
DOI: 10.1021/acs.jmedchem.5b01446

実験手法

X-RAY DIFFRACTION (2.8503 Å)