Crystal structure of A. aeolicus LpxC with bound product suggests alternate deacetylation mechanism. Issue 9 (1st August 2015)

• Record Type: Journal Article
• Authors: Miller, Matthew D.; Gao, Ning; Ross, Philip L.; Olivier, Nelson B.
• Is Part Of: Proteins. Volume 83:Issue 9(2015)
• Page Start: 1706
• Page End: 1719
• Publication Date: 2015-08-01
• Subjects: Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.24856
• Languages: English
• ISSNs: 0887-3585

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>UDP‐3‐<italic>O</italic>‐acyl‐<italic>N</italic>‐acetylglucosamine deacetylase (LpxC) is the first committed step to form lipid A, an essential component of the outer membrane of Gram‐negative bacteria. As it is essential for the survival of many pathogens, LpxC is an attractive target for antibacterial therapeutics. Herein, we report the product‐bound co‐crystal structure of LpxC from the acheal <italic>Aquifex aeolicus</italic> solved to 1.6 Å resolution. We identified interactions by hydroxyl and hydroxymethyl substituents of the product glucosamine ring that may enable new insights to exploit waters in the active site for structure‐based design of LpxC inhibitors with novel scaffolds. By using this product structure, we have performed quantum mechanical modeling on the substrate in the active site. Based on our results and published experimental data, we propose a new mechanism that may lead to a better understanding of LpxC catalysis and inhibition. Proteins 2015; 83:1706–1719. © 2015 Wiley Periodicals, Inc.</p> </abstract>