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Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors

Brannigan, JA, Roberts, SM, Bell, AS, Hutton, JA, Hodgkinson, MR, Tate, EW, Leatherbarrow, RJ, Smith, DF and Wilkinson, AJ (2014) Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors. IUCrJ, 1 (4). pp. 250-260. ISSN 2052-2525

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Abstract

The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic -carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.

Item Type: Article
Uncontrolled Keywords: Science & Technology; Physical Sciences; Technology; Chemistry, Multidisciplinary; Crystallography; Materials Science, Multidisciplinary; Chemistry; Materials Science; N-myristoyltransferase; inhibitor; ligand binding; Leishmania; drug discovery; CEREVISIAE MYRISTOYL-COA; POTENTIAL-DRUG TARGET; PLASMODIUM-FALCIPARUM; CANDIDA-ALBICANS; CRYPTOCOCCUS-NEOFORMANS; BOUND MYRISTOYLCOA; CRYSTAL-STRUCTURES; DISCOVERY; DESIGN; TRANSFERASE
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Vice-Chancellor's Office
Publisher: International Union of Crystallography
Related URLs:
Date Deposited: 19 Jun 2018 11:29
Last Modified: 16 Sep 2018 00:31
DOI or Identification number: 10.1107/S2052252514013001
URI: http://researchonline.ljmu.ac.uk/id/eprint/8855

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