4CGN

Leishmania major N-myristoyltransferase in complex with a piperidinylindole inhibitor

Summary for 4CGN

• Entry DOI: 10.2210/pdb4cgn/pdb
• Related: 4CGL 4CGM 4CGO 4CGP
• Descriptor: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, MAGNESIUM ION, 2-(4-fluorophenyl)-N-(3-piperidin-4-yl-1H-indol-5-yl)ethanamide, ... (5 entities in total)
• Functional Keywords: transferase, myristoylation, inhibitor
• Biological source: LEISHMANIA MAJOR
• Total number of polymer chains: 1
• Total formula weight: 48863.74

Authors

Brannigan, J.A.,Roberts, S.M.,Bell, A.S.,Hutton, J.A.,Smith, D.F.,Tate, E.W.,Leatherbarrow, R.J.,Wilkinson, A.J. (deposition date: 2013-11-25, release date: 2014-07-09, Last modification date: 2024-05-08)

Primary citation

Brannigan, J.A.,Roberts, S.M.,Bell, A.S.,Hutton, J.A.,Hodgkinson, M.R.,Tate, E.W.,Leatherbarrow, R.J.,Smith, D.F.,Wilkinson, A.J.
Diverse Modes of Binding in Structures of Leishmania Major N-Myristoyltransferase with Selective Inhibitors
Iucrj, 1:250-, 2014

PubMed 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 α-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.

PubMed: 25075346
DOI: 10.1107/S2052252514013001

Experimental method

X-RAY DIFFRACTION (1.69 Å)