Valentina Di Francesco
Giardia lamblia, is a single-celled, eukaryotic parasite that causes giardiasis, an infection of the small intestine that often results in diarrhea. In the United States, giardiasis is the most common intestinal parasitic disease, with upwards of 19,000 cases reported annually. Worldwide, the CDC estimates this organism infects more than 2.5 million people annually. While a number of drugs exist to treat giardiasis, potential side effects contribute to poor compliance and treatment failure. New drugs with less severe side effects and shorter dose schedules are needed to treat giardiasis or prevent its transmission.
A potential drug target identified by the Seattle Structural Genomics Center for Infectious Diseases (SSGCID) is a protein called the macrophage migration inhibitory factor (MIF). In humans, MIF is a cytokine, a proinflamatory protein that is associated with numerous diseases including cancer, diabetes, heart disease, asthma, multiple sclerosis, and rheumatoid arthritis. During some protozoan infections, including giardiasis, MIF is not only produced by the host, but has also been observed to be produced by the parasite. This has led to the hypothesis that parasitic MIF proteins may play a role in the progression of the infection and the evasion of a host immune response.
To better understand the biological role of parasitic MIF proteins, SSGCID determined the crystal structure of the MIF protein from G. lamblia at 2.30 Å resolution (PDB entry 3T5S). The 114-residue protein consists of a four-stranded beta-“sheet” with two anti-parallel alpha-helices (or spirals). The protein is trimeric, consisting of three units, and has a hole in the middle to produce a donut-like shape. It is not yet known if the channel in the donut has a biological function. Relative to the structure of the human MIF protein, there are differences in charge and in accessibility to the center of the protein that can be narrowed down primarily to two “gate-keeper” residues in the parasitic MIF. If these gate-keeper residues contribute to the biological role parasitic MIF proteins play during the progression of infection, they may also form the basis for structure-based drug design targeting parasitic MIF proteins.
Last Updated February 28, 2014