Identification of the Binding Site of Apical Membrane Antigen 1 (AMA1) Inhibitors Using a Paramagnetic Probe
Mansura Akter, Nyssa Drinkwater, Shane M Devine, Simon C Drew, Bankala Krishnarjuna, Cael O Debono, Geqing Wang, Martin J Scanlon, Peter J Scammells, Sheena McGowan, Christopher A MacRaild, Raymond S Norton
CHEMMEDCHEM | WILEY-V C H VERLAG GMBH | Published : 2019
Apical membrane antigen 1 (AMA1) is essential for the invasion of host cells by malaria parasites. Several small-molecule ligands have been shown to bind to a conserved hydrophobic cleft in Plasmodium falciparum AMA1. However, a lack of detailed structural information on the binding pose of these molecules has hindered their further optimisation as inhibitors. We have developed a spin-labelled peptide based on RON2, the native binding partner of AMA1, to probe the binding sites of compounds on PfAMA1. The crystal structure of this peptide bound to PfAMA1 shows that it binds at one end of the hydrophobic groove, leaving much of the binding site unoccupied and allowing fragment hits to bind wi..View full abstract
Awarded by Australian National Health and Medical Research Council (NHMRC)
This work was supported in part by an Australian National Health and Medical Research Council (NHMRC) project grant (1098884). R.S.N. acknowledges fellowship support from the NHMRC. We thank the Australian Synchrotron for beam-time and technical assistance. S.C.D. was supported by a fellowship awarded by the faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne.