title: Acyl chain preference and inhibitor identification of Moraxella catarrhalis LpxA: Insight through crystal structure and computational studies.
abstract: Lipopolysaccharide (LPS) is an important surface component and a potential virulence factor in the pathogenesis of Gram-negative bacteria. UDP-N-acetylglucosamine acyltransferase (LpxA) enzyme catalyzes the first reaction of LPS biosynthesis, reversible transfer of R-3-hydroxy-acyl moiety from donor R-3-hydroxy-acyl-acyl carrier protein to the 3' hydroxyl position of UDP-N-acetyl-glucosamine. LpxA enzyme's essentiality in bacterial survival and absence of any homologous protein in humans makes it a promising target for anti-bacterial drug development. Herein, we present the crystal structure of Moraxella catarrhalis LpxA (McLpxA). We propose that L171 is responsible for limiting the acyl chain length in McLpxA to 10C or 12C. The study reveals the plausible interactions between the highly conserved clusters of basic residues at the C-terminal end of McLpxA and acidic residues of acyl carrier protein (ACP). Furthermore, the crystal structure of McLpxA was used to screen potential inhibitors from NCI open database using various computational approaches viz. pharmacophore mapping, virtual screening and molecular docking. Molecules Mol212032, Mol609399 and Mol152546 showed best binding affinity with McLpxA among all screened molecules. These molecules mimic the substrate-LpxA binding interactions.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
authors.forename: Shivendra
authors.initials: S
authors.lastname: Pratap
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Kesari
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
authors.forename: Aditya
authors.initials: A
authors.lastname: Dev
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
authors.forename: Manju
authors.initials: M
authors.lastname: Narwal
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India. Electronic address: pravshai@gmail.com.
authors.forename: Pravindra
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D001936:Moraxella catarrhalis / Q000201:enzymology*; D009711:Nucleotides / Q000378:metabolism; D000072757:Protein Conformation, beta-Strand; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D009711:Nucleotides; D000217:Acyltransferases; C050304:acyl-(acyl-carrier-protein)-UDP-N-acetylglucosamine acyltransferase
keywords: Acyl carrier protein; Crystal structure; Hydrocarbon ruler; UDP-N-acetylglucosamine acyltransferase; Virtual screening