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Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines

DOI: 10.1038/s41467-020-20478-5 DOI Help

Authors: Manmohan Sharma (International Centre for Genetic Engineering and Biotechnology, India; Jamia Hamdard) , Nipun Malhotra (International Centre for Genetic Engineering and Biotechnology, India) , Manickam Yogavel (International Centre for Genetic Engineering and Biotechnology, India) , Karl Harlos (Welcome Centre for Human Genetics, University of Oxford) , Bruno Melillo (Broad Institute of Harvard and MIT; The Scripps Research Institute) , Eamon Comer (Broad Institute of Harvard and MIT) , Arthur Gonse (Broad Institute of Harvard and MIT) , Suhel Parvez (Jamia Hamdard) , Branko Mitasev (Eisai Inc) , Francis G. Fang (Eisai Inc) , Stuart L. Schreiber (Broad Institute of Harvard and MIT; Harvard University) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology, India; National Institute of Malarial Research, India)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 19946

Open Access Open Access

Abstract: 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.

Journal Keywords: Malaria; Parasitology; Target validation; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography


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