Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.
Journal Article (Journal Article)
LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.
Full Text
Duke Authors
Cited Authors
- Lee, C-J; Liang, X; Chen, X; Zeng, D; Joo, SH; Chung, HS; Barb, AW; Swanson, SM; Nicholas, RA; Li, Y; Toone, EJ; Raetz, CRH; Zhou, P
Published Date
- January 28, 2011
Published In
Volume / Issue
- 18 / 1
Start / End Page
- 38 - 47
PubMed ID
- 21167751
Pubmed Central ID
- PMC3149848
Electronic International Standard Serial Number (EISSN)
- 1879-1301
Digital Object Identifier (DOI)
- 10.1016/j.chembiol.2010.11.011
Language
- eng
Conference Location
- United States