Crystal structure of the 47-kDa lipoprotein of Treponema pallidum reveals a novel penicillin-binding protein

Ranjit K. Deka, Mischa Machius, Michael V. Norgard, Diana R. Tomchick

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 β-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 β-sheet, in contrast to the α/β-fold common to other PBPs. It comprises four distinct domains: two complex β-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 β-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.

Original languageEnglish (US)
Pages (from-to)41857-41864
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number44
DOIs
StatePublished - Nov 1 2002

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Penicillin-Binding Proteins
Treponema pallidum
Lipoproteins
Crystal structure
Penicillins
Amino Acid Motifs
Catalytic Domain
Lactams
Crystallization
Immunoglobulins
Syphilis
Sexually Transmitted Diseases
Bacteria
Amino Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Crystal structure of the 47-kDa lipoprotein of Treponema pallidum reveals a novel penicillin-binding protein. / Deka, Ranjit K.; Machius, Mischa; Norgard, Michael V.; Tomchick, Diana R.

In: Journal of Biological Chemistry, Vol. 277, No. 44, 01.11.2002, p. 41857-41864.

Research output: Contribution to journalArticle

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