Ternary structure of Plasmodium vivax N-myristoyltransferase with myristoyl-CoA and inhibitor IMP-0001173Bolling, Mendez, Taylor, Makumire, Reers, Zigweid, Subramanian, Dranow, Staker, Edwards, Tate, Bell, Myler, Asojo & Chakafana [1] Molecular Tour Plasmodium vivax is a major cause of malaria that poses an increased health burden on approximately a third of the world’s population due to climate change. Primaquine, the preferred treatment for P. vivax malaria, is contraindicated in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic cause of hemolytic anemia, affecting ~2.5% of the world’s population and ~8% the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID conducts the structure-function analysis of P. vivax N-Myristoyltransferase (PvNMT) as part of efforts to develop alternative malaria drugs. PvNMT catalyzes the attachment of myristate to the N-terminal glycine of many proteins, and this critical post-translational modification is required for P. vivax survival. The first step is forming an NMT-myristoyl-CoA binary complex that can bind to peptides. Understanding how inhibitors prevent protein binding will facilitate the development of PvNMT as a viable drug target. NMTs are secreted in all life stages of malarial parasites, making them attractive targets, unlike current antimalarials that are only effective during the plasmodial erythrocytic stages. The 2.3Å crystal structure of the ternary complex of PvNMT with Myr-CoA and a novel inhibitor is reported. The asymmetric unit contains two monomers. A view that shows Chain A (with two ligands) superimposed on it by chain B (apo). The structure reveals notable differences between PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials. ENDScript[2][3] analysis was used to identify the closest structural neighbors of PvNMT. These analyses reveal that PvNMT shares significant secondary-structural similarity with several NMTs, with identical residues observed across both the Myr-CoA- and peptide-binding domains. The regions of highest similarity are in the inter-connected Myr-CoA- and peptide-binding cavities and are shown in red on the surface diagram. Interestingly, there is a patch of white in the peptide-binding cavity. This project is part of a continuing SSGCID collaboration training Hampton University students in structural science, rational structure-based drug discovery, and scientific communication. References
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