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Crystal Structure of Low-Molecular-Weight Protein Tyrosine Phosphatase from Mycobacterium tuberculosis at 1.9-Å Resolution

Chaithanya Madhurantakam,^1, Eerappa Rajakumara,^2, Pooja Anjali Mazumdar,¹ Baisakhee Saha,¹ Devrani Mitra,¹ Harald G. Wiker,³ Rajan Sankaranarayanan,^2* and Amit Kumar Das^1*

Department of Biotechnology, Indian Institute of Technology, Kharagpur,¹ Centre for Cellular and Molecular Biology, Hyderabad, India,² The Gade Institute, University of Bergen and Haukeland University Hospital, Bergen, Norway³

Received 21 July 2004/ Accepted 10 December 2004

The low-molecular-weight protein tyrosine phosphatase (LMWPTPase) belongs to a distinctive class of phosphotyrosine phosphatases widely distributed among prokaryotes and eukaryotes. We report here the crystal structure of LMWPTPase of microbial origin, the first of its kind from Mycobacterium tuberculosis. The structure was determined to be two crystal forms at 1.9- and 2.5-Å resolutions. These structural forms are compared with those of the LMWPTPases of eukaryotes. Though the overall structure resembles that of the eukaryotic LMWPTPases, there are significant changes around the active site and the protein tyrosine phosphatase (PTP) loop. The variable loop forming the wall of the crevice leading to the active site is conformationally unchanged from that of mammalian LMWPTPase; however, differences are observed in the residues involved, suggesting that they have a role in influencing different substrate specificities. The single amino acid substitution (Leu12Thr [underlined below]) in the consensus sequence of the PTP loop, CTGNICRS, has a major role in the stabilization of the PTP loop, unlike what occurs in mammalian LMWPTPases. A chloride ion and a glycerol molecule were modeled in the active site where the chloride ion interacts in a manner similar to that of phosphate with the main chain nitrogens of the PTP loop. This structural study, in addition to identifying specific mycobacterial features, may also form the basis for exploring the mechanism of the substrate specificities of bacterial LMWPTPases.

C.M. and E.R. contributed equally to this work.

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