Structure of a novel leech carboxypeptidase inhibitor determined free in solution and in complex with human carboxypeptidase A2

Reverter, David; Fernández-Catalán, Carlos; Baumgartner, Roland; Pfänder, Ruth; Huber, Robert; Bode, Wolfram; Vendrell, Josep; Holak, Tad A.; Avilés, Francesc X.
April 2000
Nature Structural Biology;Apr2000, Vol. 7 Issue 4, p322
Academic Journal
Leech carboxypeptidase inhibitor (LCI) is a novel protein inhibitor present in the medicinal leech Hirudo medicinalis. The structures of LCI free and bound to carboxypeptidase A2 (CPA2)have been determined by NMR and X-ray crystallography, respectively. The LCI structure defines a new protein motif that comprises a five-stranded antiparallel β-sheet and one short α-helix. This structure is preserved in the complex with human CPA2 in the X-ray structure, where the contact regions between the inhibitor and the protease are defined. The C-terminal tail of LCI becomes rigid upon binding the protease as shown in the NMR relaxation studies, and it interacts with the carboxypeptidase in a substrate-like manner. The homology between the C-terminal tails of LCI and the potato carboxypeptidase inhibitor represents a striking example of convergent evolution dictated by the target protease. These new structures are of biotechnological interest since they could elucidate the control mechanism of metallo-carboxypeptidases and could be used as lead compounds for the search of fibrinolytic drugs.


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