6nxg
From Proteopedia
Crystal structure of glycylpeptide N-tetradecanoyltransferase from Plasmodium vivax in complex with inhibitor 303a
Structural highlights
FunctionA5K1A2_PLAVS Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity).[RuleBase:RU000586] Publication Abstract from PubMedNew drugs that target Plasmodium species, the causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ~1.8 million small molecules for activity against Plasmodium vivax NMT. Hits were triaged based on potency and physicochemical properties and further tested against P. vivax and P. falciparum NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of Plasmodium NMTs over human NMTs, including multiple novel scaffolds. Co-crystallization of P. vivax NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of Plasmodium NMT and serve a starting point for subsequent medicinal chemistry efforts. Identification of selective inhibitors of Plasmodium N-myristoyltransferase by high-throughput screening.,Harupa A, de Las Heras L, Colmenarejo G, Lyons-Abbott S, Reers A, Caballero Hernandez I, Chung CW, Charter D, Myler PJ, Fernandez-Menendez RM, Calderon F, Palomo S, Rodriguez B, Berlanga M, Herreros-Aviles E, Staker BL, Fernandez Alvaro E, Kaushansky A J Med Chem. 2019 Dec 18. doi: 10.1021/acs.jmedchem.9b01343. PMID:31850752[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
