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Analysis of crystal structures of aspartic proteinases: On the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes

¹ W.A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 117991, Russia
² M.M. Shemjakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117871, Russia

Reprint requests to: Natalia S. Andreeva, W.A. Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 32 Vavilov Street, Moscow 117991, Russia; e-mail: andreeva{at}genome.eimb.relarn.ru; fax: 7095-135-1405.

To elucidate the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes, we analyzed and compared the crystal structures of these enzymes, their complexes with inhibitors, and zymogens in the active site area (a total of 82 structures). In addition to the water molecule (W1) located between the active carboxyls and playing a role of the nucleophile during catalytic reaction, another water molecule (W2) at the vicinity of the active groups was found to be completely conserved. This water molecule plays an essential role in formation of a chain of hydrogen-bonded residues between the active site flap and the active carboxyls on ligand binding. These data suggest a new approach to understanding the role of residues around the catalytic site, which can assist the development of the catalytic reaction. The influence of groups adjacent to the active carboxyls is manifested by pepsin activity at pH 1.0. Some features of pepsin-like enzymes and their mutants are discussed in the framework of the approach.

Keywords: Aspartic proteases; pepsin-like enzymes; protein three-dimensional structures; comparison of protein structures; active site region of pepsin-like enzymes

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