Ternary structure of Plasmodium vivax N-myristoyltransferase with myristoyl-CoA and inhibitor IMP-0001173
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Plasmodium vivax is a major cause of malaria, which poses an increased health burden on approximately one 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, that affects ∼2.5% of the world's population and ∼8% of the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducted a 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 the survival of P. vivax. The first step is the formation of a PvNMT–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 2.3 Å resolution crystal structure of the ternary complex of PvNMT with myristoyl-CoA and a novel inhibitor is reported. One asymmetric unit contains two monomers. The structure reveals notable differences between the PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials.
Date Issued
2024-10-01
Date Acceptance
2024-08-30
Citation
Acta Crystallographica Section F: Structural Biology Communications, 2024, 80 (Part 10), pp.269-277
ISSN
2053-230X
Publisher
International Union of Crystallography
Start Page
269
End Page
277
Journal / Book Title
Acta Crystallographica Section F: Structural Biology Communications
Volume
80
Issue
Part 10
Copyright Statement
© 2024 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1107/S2053230X24008604
Subjects
Biochemical Research Methods
Biochemistry & Molecular Biology
Biophysics
Crystallography
DESIGN
G6PD deficiency
Life Sciences & Biomedicine
malaria
N-myristoyltransferases
Physical Sciences
Plasmodium vivax
Science & Technology
Publication Status
Published