Identification and Structure Solution of Fragment Hits Against Kinetoplastid N-Myristoyltransferase

Robinson D, Wyatt P, 71(Pt 5):586-93, Acta Crystallogr F Struct Biol Commun , 2015

The article describes identification of new chemical hits that could occupy DDD85646 binding site of Trypanosoma brucei N-myristoyltransferase (TbNMT). This is a therapeutic target for the treatment of human African trypanosomiasis. Fragment screening was performed by ligand-observed NMR spectroscopy. Crystal structures of the identified hits were reported in complex with closely related NMT from Leishmania major. A Pall ForteBio Octet RED384 instrument equipped with Super-Streptavidin (SSA) Biosensor probes was used to obtain the binding measurements. Biotinylated TbNMT and Leishmania major N-myristoyltransferase (LmNMT) were captured onto the SSA biosensor tip surface. The fragment hits obtained from this study are smaller and possess limited complexity. Results suggest both binding-site configurations could be induced upon ligand binding, hence demonstrating conformational plasticity of the peptide-binding site.

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