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The structural analysis of human cystatin variant, cystatin A(super 2-98) M65L, using nuclear magnetic resonance spectroscopy reveals the presence of five antiparallel beta-sheets and two short alpha-helices. The N-terminal region does not appear to influence the inhibitory action of cystatin but the changes in the conformation of the first binding loop play an important role in the inhibitory action. The conformation of the first binding loop exhibits a similarity to that of cystatin A.

A comparaison of the inhibitory activity of NH2-terminal human cysteine proteinase fused with porcine adenylate kinase shows that the amino-terminal is necessary for its activity. Removal of six residues from the amino-terminal decreases the inhibitory activity while removal of 15 residues completely inactivates the inhibitor. However the removal of the Met residue from the amino-terminal or substitution of the Pro3 with Leu residue does not affect the inhibitory activity. Substitution of the Gky75 with His residue decreases the loss of activity.