Researchers from the University of Washington working at SSRL have solved the
structure of a protein complex that may one day be exploited to combat
drug-resistant strands of the parasite that causes malaria, Plasmodium.
Malaria, one of the most devastating diseases worldwide, infects 300 to 500
million people and causes about 2 million deaths each year.
The x-ray crystallography experiments, performed at SSRL beam line 9-2 and at
the Advanced Light Source in Berkeley, California, provide atomic-level
insights into a crucial interaction occurring in a multi-protein assembly found
in the invasion machinery of the malaria parasite. A multi-protein complex
located between the parasite's plasma membrane and inner membrane complex
empowers the parasite Plasmodium to move and invade a host cell. This
complex is required for the parasite to enter and leave different types of host
cells and is highly conserved among Plasmodium variants.
The group solved the structure of a complex of Myosin A tail interacting
protein (MTIP) and MyoA-tail to 2.6 Å. The crystallized samples used contained
three different conformations of MTIP in one single crystal, which allowed the
scientists to assess the protein's crucial interaction with the MyoA-tail by
comparing three independent subunits. MTIP bridges between the membranes
associated proteins and the tail of myosin, which interacts with short actin
filaments. The actin filaments are attached to the enzyme aldolase, which
connects actin and Thrombospondin Anonymous Repeat Protein (TRAP), which
initiates the process of invasion.
The researchers performed inhibition experiments with MyoA-tail to test the
viability of P. falciparum, a dangerous malaria-causing Plasmodium species.
Because the MyoA-tail interacting P. falciparum MTIP residues differ
significantly from the human homolog, structure-based drug design can exploit
this feature and may hold promise for new therapies to combat malaria
infection. The results were published in the March 28, 2006 edition of the
Proceedings of the National Academy of Sciences.
To learn more about this research see the full scientific highlight at:
http://www-ssrl.slac.stanford.edu/research/highlights_archive/MTIP.html
Bosch, J., Turley, S., Daly, T. M., Bogh, S. M., Villasmil, M. L., Roach, C.,
Zhou, N., Morrisey, J. M., Vaidya, A. B., Bergman, L. W., et al. (2006).
Structure of the MTIP-MyoA complex, a key component of the malaria parasite
invasion motor. Proc. Natl. Acad. Sci. U.
S. A. 103, 4852-4857