Manmohan Sharma1,2, Nipun Malhotra1, Manickam Yogavel1, Karl Harlos3, Bruno Melillo4,5, Eamon Comer4, Arthur Gonse4, Suhel Parvez2, Branko Mitasev6, Francis G Fang6, Stuart L Schreiber4,7, Amit Sharma8,9. 1. Molecular Medicine, Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India. 2. Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India. 3. Division of Structural Biology, Welcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, England. 4. Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA. 5. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. 6. Eisai Inc., 35 Cambridgepark Drive Suite 200, Cambridge, MA, 02140, USA. 7. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA. 8. Molecular Medicine, Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India. directornimr@gmail.com. 9. National Institute of Malarial Research, Sector 8 Dwarka, New Delhi, 110077, India. directornimr@gmail.com.
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.
The inhibition of Plasmodium cytosolic n class="Chemical">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.
Authors: Paul D Adams; Pavel V Afonine; Gábor Bunkóczi; Vincent B Chen; Ian W Davis; Nathaniel Echols; Jeffrey J Headd; Li-Wei Hung; Gary J Kapral; Ralf W Grosse-Kunstleve; Airlie J McCoy; Nigel W Moriarty; Robert Oeffner; Randy J Read; David C Richardson; Jane S Richardson; Thomas C Terwilliger; Peter H Zwart Journal: Acta Crystallogr D Biol Crystallogr Date: 2010-01-22
Authors: Nobutaka Kato; Eamon Comer; Tomoyo Sakata-Kato; Arvind Sharma; Manmohan Sharma; Micah Maetani; Jessica Bastien; Nicolas M Brancucci; Joshua A Bittker; Victoria Corey; David Clarke; Emily R Derbyshire; Gillian L Dornan; Sandra Duffy; Sean Eckley; Maurice A Itoe; Karin M J Koolen; Timothy A Lewis; Ping S Lui; Amanda K Lukens; Emily Lund; Sandra March; Elamaran Meibalan; Bennett C Meier; Jacob A McPhail; Branko Mitasev; Eli L Moss; Morgane Sayes; Yvonne Van Gessel; Mathias J Wawer; Takashi Yoshinaga; Anne-Marie Zeeman; Vicky M Avery; Sangeeta N Bhatia; John E Burke; Flaminia Catteruccia; Jon C Clardy; Paul A Clemons; Koen J Dechering; Jeremy R Duvall; Michael A Foley; Fabian Gusovsky; Clemens H M Kocken; Matthias Marti; Marshall L Morningstar; Benito Munoz; Daniel E Neafsey; Amit Sharma; Elizabeth A Winzeler; Dyann F Wirth; Christina A Scherer; Stuart L Schreiber Journal: Nature Date: 2016-09-07 Impact factor: 49.962
Authors: Vincent B Chen; W Bryan Arendall; Jeffrey J Headd; Daniel A Keedy; Robert M Immormino; Gary J Kapral; Laura W Murray; Jane S Richardson; David C Richardson Journal: Acta Crystallogr D Biol Crystallogr Date: 2009-12-21
Authors: Joshua B Radke; Bruno Melillo; Payal Mittal; Manmohan Sharma; Amit Sharma; Yong Fu; Taher Uddin; Arthur Gonse; Eamon Comer; Stuart L Schreiber; Anil K Gupta; Arnab K Chatterjee; L David Sibley Journal: Nat Commun Date: 2022-01-24 Impact factor: 17.694