The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease |
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Authors: | Filipek Renata Rzychon Malgorzata Oleksy Aneta Gruca Milosz Dubin Adam Potempa Jan Bochtler Matthias |
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Affiliation: | International Institute of Molecular and Cell Biology, ul Trojdena 4, 02-109 Warsaw, Poland. |
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Abstract: | 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 beta-barrel with statistically significant similarity to lipocalins, but not to cystatins. We now present the 1.8-A 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 A2. 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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