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Protein Science (2006), 15:2002-2007. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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PROTEIN STRUCTURE REPORT

The product complex of M. tuberculosis malate synthase revisited

David M. Anstrom and S. James Remington

Institute of Molecular Biology, Departments of Chemistry and Physics, University of Oregon, Eugene, Oregon 97403, USA

(RECEIVED April 20, 2006; FINAL REVISION May 16, 2006; ACCEPTED May 16, 2006)

Enzymes of the glyoxylate shunt have been implicated as virulence factors in several pathogenic organisms, notably Mycobacterium tuberculosis and Candida albicans. Malate synthase has thus emerged as a promising target for design of anti-microbial agents. For this effort, it is essential to have reliable models for enzyme:substrate complexes. A 2.7 Å resolution crystal structure for M. tuberculosis malate synthase in the ternary complex with magnesium, malate, and coenzyme A has been previously described. However, some unusual aspects of malate and Mg++ binding prompted an independent determination of the structure at 2.3 Å resolution, in the presence of saturating concentrations of malate. The electron density map of the complex reveals the position and conformation of coenzyme A to be unchanged from that found in the previous study. However, the coordination of Mg++ and orientation of bound malate within the active site are different. The revised position of bound malate is consistent with a reaction mechanism that does not require reorientation of the electrophilic substrate during the catalytic cycle, while the revised Mg++ coordination is octahedral, as expected. The results should be useful in the design of malate synthase inhibitors.

Keywords: malate synthase; protein crystallography; mycobacterium tuberculosis; drug design; ternary complex


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