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The inhibition of Plasmodium cytosolic phenylalanine tRNA-synthetase (cFRS) by a novel series of bicyclic azetidines has shown the potential to prevent malaria transmission, provide prophylaxis, and offer single-dose cure in animal models of malaria. To date, however, the molecular basis of Plasmodium cFRS inhibition by bicyclic azetidines has remained unknown. Here, we present structural and biochemical evidence that bicyclic azetidines are competitive inhibitors of L-Phe, one of three substrates required for the cFRS-catalyzed aminoacylation reaction that underpins protein synthesis in the parasite. Critically, our co-crystal structure of a PvcFRS-BRD1389 complex shows that the bicyclic azetidine ligand binds to two distinct sub-sites within the PvcFRS catalytic site. The ligand occupies the L-Phe site along with an auxiliary cavity and traverses past the ATP binding site. Given that BRD1389 recognition residues are conserved amongst apicomplexan FRSs, this work lays a structural framework for the development of drugs against both Plasmodium and related apicomplexans.

Original publication

DOI

10.1038/s41467-020-20478-5

Type

Journal article

Journal

Nature communications

Publication Date

12/01/2021

Volume

12

Addresses

Molecular Medicine, Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India.

Keywords

Cytosol, Animals, Parasites, Plasmodium falciparum, Malaria, Azetidines, Phenylalanine-tRNA Ligase, Phenylalanine, Enzyme Inhibitors, Amino Acid Sequence, Catalytic Domain, Aminoacylation, Drug Resistance, Mutation, Models, Molecular