7T5R

P. aeruginosa LpxA in complex with ligand H7

Summary for 7T5R

• Entry DOI: 10.2210/pdb7t5r/pdb
• Descriptor: Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase, 3-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]-1H-indole-5-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: lpxa, lipid a, lps, lipopolysaccharide, udp-n-acetylglucosamine o-acyltransferase, transferase
• Biological source: Pseudomonas aeruginosa PA7
• Total number of polymer chains: 6
• Total formula weight: 171066.89

Authors

Sacco, M.,Chen, Y. (deposition date: 2021-12-13, release date: 2022-07-06, Last modification date: 2023-10-18)

Primary citation

Sacco, M.D.,Defrees, K.,Zhang, X.,Lawless, W.,Nwanochie, E.,Balsizer, A.,Darch, S.E.,Renslo, A.R.,Chen, Y.
Structure-Based Ligand Design Targeting Pseudomonas aeruginosa LpxA in Lipid A Biosynthesis.
Acs Infect Dis., 8:1231-1240, 2022

PubMed Abstract: Enzymes involved in lipid A biosynthesis are promising antibacterial drug targets in Gram-negative bacteria. In this study, we use a structure-based design approach to develop a series of novel tetrazole ligands with low μM affinity for LpxA, the first enzyme in the lipid A pathway. Aided by previous structural data, X-ray crystallography, and surface plasmon resonance bioanalysis, we identify 17 hit compounds. Two of these hits were subsequently modified to optimize interactions with three regions of the LpxA active site. This strategy ultimately led to the discovery of ligand L13, which had a of 3.0 μM. The results reveal new chemical scaffolds as potential LpxA inhibitors, important binding features for ligand optimization, and protein conformational changes in response to ligand binding. Specifically, they show that a tetrazole ring is well-accommodated in a small cleft formed between Met169, the "hydrophobic-ruler" and His156, both of which demonstrate significant conformational flexibility. Furthermore, we find that the acyl-chain binding pocket is the most tractable region of the active site for realizing affinity gains and, along with a neighboring patch of hydrophobic residues, preferentially binds aliphatic and aromatic groups. The results presented herein provide valuable chemical and structural information for future inhibitor discovery against this important antibacterial drug target.

PubMed: 35653508
DOI: 10.1021/acsinfecdis.1c00650

Experimental method

X-RAY DIFFRACTION (1.95 Å)