Journal of Biological Chemistry
Volume 278, Issue 42, 17 October 2003, Pages 40959-40966
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Enzyme Catalysis and Regulation
The Staphostatin-Staphopain Complex: A FORWARD BINDING INHIBITOR IN COMPLEX WITH ITS TARGET CYSTEINE PROTEASE*

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Staphostatins are the endogenous inhibitors of the major secreted cysteine proteases of Staphylococcus aureus, the staphopains. Our recent crystal structure of staphostatin B has shown that this inhibitor forms a mixed, eight-stranded β-barrel with statistically significant similarity to lipocalins, but not to cystatins. We now present the 1.8-Å crystal structure of staphostatin B in complex with an inactive mutant of its target protease. The complex is held together through extensive interactions and buries a total surface area of 2300 Å2. Unexpectedly for a cysteine protease inhibitor, staphostatin B binds to staphopain B in an almost substrate-like manner. The inhibitor polypeptide chain runs through the protease active site cleft in the forward direction, with residues IG-TS in P2 to P2′ positions. Both in the free and complexed forms, the P1 glycine residue of the inhibitor is in a main chain conformation only accessible to glycines. Mutations in this residue lead to a loss of affinity of the inhibitor for protease and convert the inhibitor into a substrate.

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

*

This work was supported by the Commission of the European Communities, specific RTD program “Quality of Life and Management of Living Resources,” QLRT-2001-01250, “Novel non-antibiotic treatment of staphylococcal diseases,” and Committee for Scientific Investigation (KBN) Grants 6P04A08320, 1789/E-529/SPB/5.PR UE/DZ 600/2002-2005, and 158/E-338/SPB/5.PR UE/DZ 19/2003. 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.

Both authors contributed equally to the results of this work.