4U3B

LpxC from A.Aaeolicus in complex with the MMP inhibitor 4-[[4-(4-chlorophenoxy)phenyl]sulfanylmethyl]tetrahydropyran-4-carbohydroxamic acid - compound 2

4U3B の概要

• エントリーDOI: 10.2210/pdb4u3b/pdb
• 分子名称: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, IMIDAZOLE, ZINC ION, ... (6 entities in total)
• 機能のキーワード: antibacterial, lpxc, gram negative bacteria, mmp, hydrophobe, hydrolase
• 由来する生物種: Aquifex aeolicus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31654.20

構造登録者

Olivier, N.B. (登録日: 2014-07-19, 公開日: 2014-10-01, 最終更新日: 2024-05-08)

主引用文献

Murphy-Benenato, K.E.,Olivier, N.,Choy, A.,Ross, P.L.,Miller, M.D.,Thresher, J.,Gao, N.,Hale, M.R.
Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.
Acs Med.Chem.Lett., 5:1213-1218, 2014

PubMed Abstract: In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.

PubMed: 25408833
DOI: 10.1021/ml500210x

実験手法

X-RAY DIFFRACTION (1.34 Å)