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Citation

BibTex format

@article{Brannigan:2014:10.1107/S2052252514013001,
author = {Brannigan, JA and Roberts, SM and Bell, AS and Hutton, JA and Hodgkinson, MR and Tate, EW and Leatherbarrow, RJ and Smith, DF and Wilkinson, AJ},
doi = {10.1107/S2052252514013001},
journal = {IUCrJ},
pages = {250--260},
title = {Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors},
url = {http://dx.doi.org/10.1107/S2052252514013001},
volume = {1},
year = {2014}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - The leishmaniases are a spectrum of global diseases of poverty associated withimmune dysfunction and are the cause of high morbidity. Despite the longhistory of these diseases, no effective vaccine is available and the currently useddrugs are variously compromised by moderate efficacy, complex side effects andthe emergence of resistance. It is therefore widely accepted that new therapiesare needed. N-Myristoyltransferase (NMT) has been validated pre-clinically asa target for the treatment of fungal and parasitic infections. In a previouslyreported high-throughput screening program, a number of hit compounds withactivity against NMT from Leishmania donovani have been identified. Here,high-resolution crystal structures of representative compounds from four hitseries in ternary complexes with myristoyl-CoA and NMT from the closelyrelated L. major are reported. The structures reveal that the inhibitors associatewith the peptide-binding groove at a site adjacent to the bound myristoyl-CoAand the catalytic -carboxylate of Leu421. Each inhibitor makes extensiveapolar contacts as well as a small number of polar contacts with the protein.Remarkably, the compounds exploit different features of the peptide-bindinggroove and collectively occupy a substantial volume of this pocket, suggestingthat there is potential for the design of chimaeric inhibitors with significantlyenhanced binding. Despite the high conservation of the active sites of theparasite and human NMTs, the inhibitors act selectively over the host enzyme.The role of conformational flexibility in the side chain of Tyr217 in conferringselectivity is discussed.
AU - Brannigan,JA
AU - Roberts,SM
AU - Bell,AS
AU - Hutton,JA
AU - Hodgkinson,MR
AU - Tate,EW
AU - Leatherbarrow,RJ
AU - Smith,DF
AU - Wilkinson,AJ
DO - 10.1107/S2052252514013001
EP - 260
PY - 2014///
SN - 2052-2525
SP - 250
TI - Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors
T2 - IUCrJ
UR - http://dx.doi.org/10.1107/S2052252514013001
UR - http://hdl.handle.net/10044/1/26922
VL - 1
ER -

Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821