High-resolution NMR studies of apical membrane antigen 1 (AMA1), a target for antimalarial drug development — ASN Events
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High-resolution NMR studies of apical membrane antigen 1 (AMA1), a target for antimalarial drug development (#105)

Krishnarjuna Bankala 1 , San Sui Lim 1 , Christopher A MacRaild 1 , Indu Chandrashekaran 1 , Hanudatta S Atreya 2 , Raymond S Norton 1
  1. Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  2. NMR Research Center, Indian Institute of Science, Bangalore, Karnataka, India

Apical membrane antigen 1 (AMA1) is a protein of the Plasmodium parasite that is involved in the formation of the moving junction during red blood cell invasion (1). Invasion inhibitory molecules like R1 peptide and anti-AMA1 antibodies target a conserved hydrophobic cleft on AMA1 and block the invasion process. Thus, AMA1 has become a target for drug development (2). Here we describe the application of solution NMR spectroscopy to study AMA1-small molecule interactions. Based on perturbations in specific chemical shifts in the NMR spectrum of AMA1, it is feasible to map the binding sites for ligand/small inhibitory molecules, facilitating the design of new drugs to treat malaria.

AMA1 is a high molecular mass (42 kDa) protein, making resonance assignments particularly challenging because of peak overlap. We have used different isotope labelling approaches (3, 4) and regular TROSY-based triple resonance NMR experiments to obtain residue-specific and sequential assignments, respectively. The results from chemical shift analysis of AMA1 and their importance in mapping the binding sites on AMA1 for small inhibitory molecules will be presented.

  1. Tonkin ML, et al. (2011) Host cell invasion by apicomplexan parasites: insights from the co-structure of AMA1 with a RON2 peptide. Science 333:463-467.
  2. MacRaild CA, Anders RF, Foley M, & Norton RS (2011) Apical membrane antigen 1 as an anti-malarial drug target. Curr. Top. Med. Chem. 11:2039-2047.
  3. Hiroaki H (2013) Recent applications of isotopic labeling for protein NMR in drug discovery. Expert Opin. Drug Discov. 8:523-536.
  4. Krishnarjuna B, Jaipuria G, Thakur A, D’Silva P, & Atreya HS (2011) Amino acid selective unlabelling for sequence specific resonance assignments in proteins. J. Biomol. NMR 49:39-51.