Eukaryotic and retroviral aspartic proteases: similarities and differences

Abstract

The superfamily of aspartic proteases consists of two large families, eukaryotic and retroviral. Eukaryotic enzymes are encoded as single chains with two‐domain structures, whereas retroviral enzymes are active as homodimers. Both families include enzymes of considerable medical relevance, thus a vast number of structures of their inhibitor complexes have been reported. Whereas some of these inhibitors are very specific for particular members of each family, others are pleuripotent. For example, recent findings of cross‐reactivity of potent inhibitors of HIV‐1 PR and plasmepsin emphasized the need to evaluate the inhibitor complexes of other aspartic proteases from both families in an effort to create novel inhibitors. Such a task is hindered by the large differences in size between proteins from two families, and additionally complicated by the deviation in the symmetry of the functional subunits. We succeeded in generating very accurate overall superposition of these enzymes, including the ligands bound in their active sites. That allows us to evaluate an overall fit and the interactions of any inhibitor, which has been developed for one family member (e.g. HIV‐1 PR), in respect to the other family (e.g. renin). We are also able to characterize the structural similarities and differences between the two families with much higher accuracy, addressing their functional and evolutionary significance.