Conformational diversity of bacterial FabH: Implications for molecular recognition specificityby Anuradha Mittal, Michael E. Johnson

Journal of Molecular Graphics and Modelling

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Journal of Molecular Graphics and Modelling 55 (2015) 115–122

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Conformational diversity of bacterial FabH: Impli recognition specificity

Anuradha Mittal1, Michael E. Johnson ∗

Center for Phar 0, Chi a r t i c l

Article history:

Accepted 7 No

Available onlin

Keywords:

FabH

Conformation

Binding specifi

Computationa ate a iffer tiona s Gra

H fro iors. D ent m r data nces t s wil nzym 1. Introduction

The incr urgent need be used to bacterial ty as a promi fatty acid b bacteria. Th essential fo of the bact malian mul antimicrobi

Further, sev targeting FA pathway as

Abbreviatio

FabH; efFabH, synthase; MD born surface a ∗ Correspon

E-mail add 1 Present ad ical Systems E -Ketoacyl-acyl carrier protein synthase III (FabH) is an essenhttp://dx.doi.o 1093-3263/© easing resistance to available antibiotics has led to an for the discovery of novel modes of action that could combat drug-resistant microbial strains. Recently, the pe II fatty acid synthase (FASII) system has emerged sing novel antibiotic target. FASII enzymes carry out iosynthesis and regulate the fatty acid composition of e membrane lipid biosynthesis and its homeostasis are r bacterial survival [1]. The organization and structure erial FASII system is distinct from that of the mamtienzyme type I system, offering selective inhibition by al agents and reduced risks of nonspecific toxicity [2,3]. eral natural product [4–7] and synthetic inhibitors [8,9]

SII enzymes have demonstrated the validity of the FASII an antibiotic target. ns: CSM, computational solvent mapping; ecFabH, Escherichia coli

Enterococcus faecalis FabH; FAB, fatty acid biosynthesis; FAS, fatty acid , molecular dynamics; MM-GBSA, molecular mechanics-generalized rea; PDB, Protein Data Bank; RMSD, root mean squared deviation. ding author. Tel.: +1 312 996 9114; fax: +1 312 431 9303. ress: mjohnson@uic.edu (M.E. Johnson). dress: Department of Biomedical Engineering and Center for Biologngineering, Washington University in St. Louis, MO 63112, USA. tial enzyme in the FASII pathway, which catalyzes the first step in the pathway, the condensation of acyl-CoA primers with malonylACP. FabH from Gram-positive and Gram-negative bacteria are known to have distinct preferences for acyl-CoA primers. This is functionally important, as the substrate specificity of the enzyme governs the fatty acid profile of the organism [10]. FabH from E. coli and other Gram-negative organisms are selective for acetyl-CoA and produce straight-chain fatty acids, while the FabH enzymes of Gram-positive bacteria such as bacilli prefer branched-chain primers and produce branched-chain fatty acids. The differential ligand specificity across homologs has also been observed in

FabH drug design [11]. The identified FabH inhibitors show varied inhibitory potencies for FabH from different bacterial species [11]. The origin of the observed inter-species variability of substrate and inhibitor activity is not obvious. The substrate binding cleft of FabH is predominantly lined by hydrophobic residues that form the majority of protein–ligand interactions in the co-crystal structures. A few hydrogen bonds with the polar and charged residues at the base and at the entrance of the pocket are the likely interactions that define the binding specificity in these complexes. However, the sequences and the structures of the FabH substrate-binding pockets are highly conserved across bacterial genomes. Out of the 24 residues of the FabH binding pocket that lie within 5 A˚ of any atom of the inhibitor in the E. coli rg/10.1016/j.jmgm.2014.11.004 2014 Elsevier Inc. All rights reserved.maceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Ave—m/c 87 e i n f o vember 2014 e 15 November 2014 al diversity city l solvent mapping a b s t r a c t

The molecular basis of variable substr acid synthase enzyme, FabH, across d rent work, we explored the conforma of diverse interaction specificity acros dynamics simulations reveal that Fab tional ensembles and dynamic behav assessment using computational solv tions between the two homologs. Ou minor sequence and structural differe across bacterial species. These insight antibacterial inhibitors against FabH ecations for molecular cago, IL 60607-7173, USA nd inhibitor specificity of the highly conserved bacterial fatty ent bacterial species remains poorly understood. In the curl diversity of FabH enzymes to understand the determinants m-positive and Gram-negative bacteria. Atomistic molecular m E. coli and E. faecalis exhibit distinct native state conformaespite strikingly similar substrate binding pockets, hot spot apping identified quite different favorable binding interacsuggest that FabH utilizes protein dynamics and seemingly o modulate its molecular recognition and substrate specificity l potentially facilitate the rational design and development of es. © 2014 Elsevier Inc. All rights reserved. 116 A. Mittal, M.E. Johnson / Journal of Molecular Graphics and Modelling 55 (2015) 115–122

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