Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 6419 - 6427 |
| Number of pages | 9 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 57 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Ligand-induced conformational change of Plasmodium falciparum AMA1 detected using 19F NMR. / Ge, Xiaopeng; MacRaild, Christopher Andrew; Devine, Shane; Debono, Cael; Wang, Geqing; Scammells, Peter John; Scanlon, Martin; Anders, Robin F; Foley, Michael; Norton, Raymond Stanley.
In: Journal of Medicinal Chemistry, Vol. 57, No. 15, 2014, p. 6419 - 6427.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Ligand-induced conformational change of Plasmodium falciparum AMA1 detected using 19F NMR
AU - Ge, Xiaopeng
AU - MacRaild, Christopher Andrew
AU - Devine, Shane
AU - Debono, Cael
AU - Wang, Geqing
AU - Scammells, Peter John
AU - Scanlon, Martin
AU - Anders, Robin F
AU - Foley, Michael
AU - Norton, Raymond Stanley
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://pubs.acs.org/doi/pdf/10.1021/jm500390g
U2 - 10.1021/jm500390g
DO - 10.1021/jm500390g
M3 - Article
VL - 57
SP - 6419
EP - 6427
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 15
ER -