Crucial Elements for Designing a Malaria Vaccine are Revealed by the Structure of Apical Membrane Antigen 1

07-06-2005

Malaria causes more than 2 million deaths each year and, along with AIDS and tuberculosis, is one of the three "diseases of poverty". With the growing problem of resistance to anti-malarial drugs, the search for alternative strategies for combating the disease has become urgent.

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The development of an effective vaccine has therefore received much attention in recent years. A number of surface proteins from Plasmodium, the unicellular parasite that causes the disease, show promise as vaccines, and Apical Membrane Antigen 1 (AMA1) is one such candidate currently in clinical trials. The precise biological function of AMA1 is unknown but it is essential for invasion of host cell (liver cells and red blood cells) by the parasite. Indeed, antibodies induced by AMA1 prevent parasite invasion, providing the principal mechanism of protection against the disease when this antigen is use for immunisation. The crystal structure of AMA1 has been determined from crystallographic experiments carried out at the macromolecular crystallography beamlines BM14 (UK/EMBL funded CRG beamline at the ESRF) and ID14-4 (an ESRF public beamline). The structure has provided detailed information on the 3-dimensional distribution of polymorphic residues on the surface of the molecule and has pinpointed a region of the protein that is recognised by an invasion-inhibitory antibody. Moreover, the structure of AMA1 furnishes a basis to design further experiments to understand its biological function in molecular detail. Knowledge of this kind is important in optimising this candidate antigen as a vaccine.

Ribbons representation of the structure of apical membrane antigen 1 from Plasmodium vivax

Ribbons representation of the structure of apical membrane antigen 1 from Plasmodium vivax.

 

 

Authors and Principal Publication
J.C. Pizarro (a), B. Vulliez-Le Normand (a), M.L. Chesne-Seck (a), C.R. Collins (b), C. Withers-Martinez (b), F. Hackett (b), M.J. Blackman (b), B.W. Faber (c), E.J. Remarque (c), C.H.M. Kocken (c), A.W. Thomas (c) and G.A. Bentley (a), Science 308, 408-411 (2005).
a) Unité d'Immunologie Structurale, Centre National de la Recherche Scientifique, URA 2185, Institut Pasteur, Paris (France)
b) Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill (UK)
c) Department of Parasitology, Biomedical Primate Research Centre, Rijswijk (Netherlands)