Structural analysis of carboxypeptidase A and its complexes with inhibitors as a basis for modeling enzyme recognition and specificity

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Abstract
A combination of novel methods of macrostructural analysis and theoretical chemistry were applied to study the metalloenzyme carboxypeptidase A and its complexes with two inhibitors—glycyl‐L‐tyrosine and a protein inhibitor isolated from potatoes. The methods of macrostructural analysis applied to the study of the crystal structures of these molecules include structural superposition, distance matrix analysis, and linear distance plot analysis, and the approach is complemented by the examination of computed physicochemical properties, including electrostatic potential surfaces, bulk hydrophobicity, and complementarity of van der Waals surfaces. The structural analysis identified folding domains in carboxypeptidase A that relate to such domains in carboxypeptidase B and are involved in the conformational changes following complexation with the inhibitors. The nature of these conformational changes and their relation to the physicochemical properties suggest their role in determining recognition and reactivity characteristics of the enzyme. The analysis also revealed a distinction between conformational changes in the secondary and tertiary structure of the protein that provides insight into the structure–function relationship in carboxypeptidase. Notably, some inhibitor‐induced changes in structure occur in regions in which the interacting molecules are not in contact, while some of the contact regions, such as the active site, incur only minor perturbation. The analysis reveals the interrelation between the enzyme–ligand interaction and the structural perturbation outside the active site, thus illuminating one aspect of the link between the structural organization of the protein and its function.

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