Crystallization of the Galactosyltransferase from Mtb

Southern Research Institute, Birmingham AL

Investigators

Abstract

DESCRIPTION (provided by applicant): This application is in response to PAS-02-031 for a supplement to our current NIAID-funded program AI45317 entitled Glycosyltransferases as Drug Targets in Mycobacteria. This supplemental program will involve the expression, purification, and crystallization of the galactosyltransferase (Rv3808c) from Mycobacterium tuberculosis. The galactosyltransferase adds galactofuranose units to the growing galactan, a polysaccharide that anchors the mycolylarabinan superstructure and is critical to mycobacterial cell wall integrity in the harsh environment of the human macrophage. This effort is responsive to the announcement in that it supplements our current program by applying modern structural biology techniques to obtain a structure of a protein targeted for drug development under our current grant. This protein was not available at the time of our application, and the information provided through the application of the requested supplemental funds will give us a specific picture of the protein active site allowing more rapid development of drugs to target this critical mycobacterial enzyme. As well, this grant is responsive to the PA in that it addresses a new drug target in tuberculosis, and may have implications in the treatment of multi-drug resistant tuberculosis (MDR-TB), a critical health problem worldwide. Tuberculosis and its drug resistant forms are the focus of two active NIAID Program Announcements (PA-99-124 & PA-01-113) and is considered a potential biological weapon by the Department of Defense. This application involves modern structural biology that may not be considered as innovative as recent techniques in bioinformatics, genomics, and microarray technology. This effort, however, is innovative in the choice of target and the impact that structural biology can have on our funded program.