A New Type of Aspartic Proteinase Inhibitors with a Symmetric Structure
Molecules of aspartic proteinases of mammalian and fungal origin are known to consist of one polypeptide chain forming two structurally similar domains.1–3 The molecules in whole possess pseudosymmetric structure with two-fold axis of symmetry. In contrast to cellular aspartic proteinases, the enzymes of retroviruses can function in the form of homodimers only.4,5 The active site is formed during dimerization so that each subunit contributes one Asp25 residue to the catalytic site. Thus the active molecule is perfectly symmetric. At the same time the substrates of the enzyme are not symmetric as peptide chains are always directed. So in the active site of a retroviral proteinase the productive binding of the substrate is possible both “from east to west” and vise versa, “from west to east”. X-ray analysis studies have revealed that binding of inhibitors and, most likely, substrates causes significant conformational changes in aspartic proteinases.6–8 In the case of HIV proteinase such changes were shown to disturb the symmetry of the molecule.9,10 But this may not be necessary in the case of binding of a symmetric inhibitor, and symmetric structures may have a significant advantage both in affinity and in selectivity, as the degree of symmetry is much higher for the viral enzymes compared to cellular ones.
KeywordsAspartic Proteinase Anthranilic Acid Peptide Moiety Significant Conformational Change Productive Binding
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