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Originally published In Press as doi:10.1074/jbc.M207402200 on August 24, 2002

J. Biol. Chem., Vol. 277, Issue 44, 41857-41864, November 1, 2002
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Crystal Structure of the 47-kDa Lipoprotein of Treponema pallidum Reveals a Novel Penicillin-binding Protein*

Ranjit K. DekaDagger , Mischa Machius§, Michael V. NorgardDagger , and Diana R. Tomchick§

From the Departments of Dagger  Microbiology and § Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Syphilis is a complex sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum. T. pallidum has remained exquisitely sensitive to penicillin, but the mode of action and lethal targets for beta -lactams are still unknown. We previously identified the T. pallidum 47-kDa lipoprotein (Tp47) as a penicillin-binding protein (PBP). Tp47 contains three hypothetical consensus motifs (SVTK, TEN, and KTG) that typically form the active center of other PBPs. Yet, in this study, mutations of key amino acids within these motifs failed to abolish the penicillin binding activity of Tp47. The crystal structure of Tp47 at a resolution of 1.95 Å revealed a fold different from any other known PBP; Tp47 is predominantly beta -sheet, in contrast to the alpha /beta -fold common to other PBPs. It comprises four distinct domains: two complex beta -sheet-containing N-terminal domains and two C-terminal domains that adopt immunoglobulin-like folds. The three hypothetical PBP signature motifs do not come together to form a typical PBP active site. Furthermore, Tp47 is unusual in that it displays beta -lactamase activity (kcat for penicillin = 271 ± 6 s-1), a feature that hindered attempts to identify the active site in Tp47 by co-crystallization and mass spectrometric techniques. Taken together, Tp47 does not fit the classical structural and mechanistic paradigms for PBPs, and thus Tp47 appears to represent a new class of PBP.

* This work was supported by Grant AI-16692 from the NIAID, National Institutes of Health, and by Grant I-0940 from the Robert A. Welch Foundation. Use of the Argonne National Laboratory Structural Biology Center beamline at the Advanced Photon Source was supported by the United States Department of Energy, Office of Biological and Environmental Research, under Contract W-31-109-ENG-38.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Microbiology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390. Tel.: 214-648-5900; Fax: 214-648-5905; E-mail: michael.norgard@utsouthwestern.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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