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J. Biol. Chem., Vol. 279, Issue 35, 36771-36777, August 27, 2004

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Mycobacterium tuberculosis Antigen 85A and 85C Structures Confirm Binding Orientation and Conserved Substrate Specificity^*

Donald R. Ronning, Varalakshmi Vissa¶, Gurdyal S. Besra||**, John T. Belisle¶, and James C. Sacchettini

From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, the ^||School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, and the ^¶Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523

The maintenance of the highly hydrophobic cell wall is central to the survival of Mycobacterium tuberculosis within its host environment. The antigen 85 proteins (85A, 85B, and 85C) of M. tuberculosis help maintain the integrity of the cell wall 1) by catalyzing the transfer of mycolic acids to the cell wall arabinogalactan and 2) through the synthesis of trehalose dimycolate (cord factor). Additionally, these secreted proteins allow for rapid invasion of alveolar macrophages via direct interactions between the host immune system and the invading bacillus. Here we describe two crystal structures: the structure of antigen 85C co-crystallized with octylthioglucoside as substrate, resolved to 2.0 Å, and the crystal structure of antigen 85A, which was solved at a resolution of 2.7 Å. The structure of 85C with the substrate analog identifies residues directly involved in substrate binding. Elucidation of the antigen 85A structure, the last of the three antigen 85 homologs to be solved, shows that the active sites of the three antigen 85 proteins are virtually identical, indicating that these share the same substrate. However, in contrast to the high level of conservation within the substrate-binding site and the active site, surface residues disparate from the active site are quite variable, indicating that three antigen 85 enzymes are needed to evade the host immune system.

Received for publication, January 25, 2004 , and in revised form, June 8, 2004.

^* This work was supported in part by the Robert A. Welch Foundation and by Grant GM62410 from the National Institutes of Health. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the Office of Energy Research, United States Department of Energy, under Contract W-31-109-ENG-38. Use of the BioCARS Sector 14 was supported by the National Institutes of Health, National Center for Research Resources, under Grant RR07707. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (codes 1SFR and 1VA5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Present address: Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892.

^** Currently a Lister Jenner Research Fellow and supported by the Medical Research Council.

To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, Texas A&M University, 2128 TAMU, College Station, TX 77843-2128. Tel.: 979-862-7636; Fax: 979-862-7638; E-mail: sacchett{at}tamu.edu.

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