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For example, in the specificity subsite S 3 the phenyl rings of Phe P 3 occupy almost identical positions in
both renin inhibitor complexes. Modeling studies have predicted the specificity subsite S 3 to be larger in
renins than in other aspartic proteinases [4] due to substitution of smaller residues, Pro 111, Leu114, and
Ala115, in place of larger ones in mammalian and fungal proteinases. However, a compensatory
movement of a helix (h N2) makes the pocket quite compact and complementary to the aromatic ring as
shown in Figure 5. Thus, the positions of an element of secondary structure differ between renin and
other aspartic proteinases with a consequent important difference in the specificity pocket.
The differing positions of secondary structural elements may also account for the specificities at P 2'.
Mouse submaxillary and other nonprimate renins do not appreciably cleave human angiotensinogen or
its analogs [46], which have an isoleucine at P 2', although they do cleave substrates with a valine at this
position. In contrast, human renin not only cleaves the human and nonprimate substrates but also the rat
angiotensinogen with tyrosine at P 2', albeit rather slowly [47]. This can be explained in terms of the threedimensional
structures. In the mouse renin complex, the P 2' tyrosyl ring is packed parallel to an
adjoining helix (h 3) in a narrow pocket and there is only limited space available beyond the Cβ
methylene group. This appears to be able to accommodate a valine, but not the larger isoleucine at P 2',
which will suffer greater steric interference from several residues that are conserved in identity and
position in the two renins. On the other hand, in human renin differences in the orientation and position
of
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