Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases.
1999
Three α-mercaptoacyldipeptides differing essentially in the size of their C-terminal residues have been crystallized in the thermolysin active site. A new mode of binding was observed for 3 [HS-CH(CH2Ph)CO-Phe-Tyr] and 4 [HS-CH((CH2)4CH3)CO-Phe-Ala], in which the mercaptoacyl moieties act as bidentates with Zn−S and Zn−O distances of 2.3 and 2.4 A, respectively, the side chains fitting the S1, S1‘, and S2‘ pockets. Moreover, a distance of 3.1 A between the sulfur atom and the OE1 of Glu143 suggests that they are H-bonded and that one of these atoms is protonated. This H-bond network involving Glu143, the mercaptoacyl group of the inhibitor, and the Zn ion could be considered a “modified” transition state mimic of the peptide bond hydrolysis. Due to the presence of the hindering (5-phenyl)proline, the inhibitor HS-CH(CH2Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation via the thiol group and occupancy of S1‘ and S2‘ subsites by the aromatic moieties, the proline ring being outside the a...
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