Ligand-induced conformational change of Plasmodium falciparum AMA1 detected using 19F NMR

Xiaopeng Ge, Christopher Andrew MacRaild, Shane Devine, Cael Debono, Geqing Wang, Peter John Scammells, Martin Scanlon, Robin F Anders, Michael Foley, Raymond Stanley Norton

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)

Abstract

We established an efficient means of probing ligand-induced conformational change in the malaria drug target AMA1 using 19F NMR. AMA1 was labeled with 5-fluorotryptophan (5F-Trp), and the resulting 5F-Trp resonances were assigned by mutagenesis of the native Trp residues. By introducing additional Trp residues at strategic sites within a ligand-responsive loop, we detected distinct conformational consequences when various peptide and small-molecule ligands bound AMA1. Our results demonstrate an increase in flexibility in this loop caused by the native ligand, as inferred from, but not directly observed in, crystal structures. In addition, we found evidence for long-range allosteric changes in AMA1 that are not observed crystallographically. This method will be valuable in ongoing efforts to identify and characterize therapeutically relevant inhibitors of protein-protein interactions involving AMA1 and is generalizable to the study of ligand-induced conformational change in a wide range of other drug targets.
Original languageEnglish
Pages (from-to)6419 - 6427
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number15
DOIs
Publication statusPublished - 2014

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