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plasma. This may arise from reduced nonspecific plasma binding due to the relatively polar nature of
these blocking groups [24].
Page 331
Resistance of inhibitors to gut proteolysis has been improved by various methods such as replacement of
phenylalanine at P 3 with O-methyl tyrosine (or naphthylalanine), which was shown to abolish
chymotrypsin cleavage and yet retain high inhibitory potency for renin [40].
III. Structural Studies of Rennin Complexed With Inhibitors
The three-dimensional structures of renin-inhibitor complexes had long been sought as an aid to the
discovery of clinically effective antihypertensives [41]. X-ray analyses of recombinant human renin [42]
and mouse submandibulary renin [43] have given an accurate picture of active-site interactions and
largely confirm the predictions of models based on homologous aspartic proteinases [4]. A large number
of questions concerning the specificities of renins have been answered by these x-ray analyses. The
renin-inhibitor structures also make an important contribution towards the rational design of effective
antihypertensive agents.
A. X-Ray Analysis of Mouse and Human Renin Complexes
For both of these renins multiple copies of the molecules have been independently defined in the x-ray
analysis and shown to have very similar structures. These x-ray structures were refined to final
agreement factors and correlation coefficients of 0.19 and 0.91 for human renin at 2.8 Å resolution and
0.18 and 0.95 for mouse renin at 1.9 Å resolution. As expected from the high degree of sequence
identity of human and mouse renins (approximately 70%), they have very similar three-dimensional
structures as shown in Figure 1.
The active-site cleft has a less open arrangement in renins than in the other aspartic proteinases. Many
loops as well as the helix h c (residues 224–236) belonging to the C-domain (residues 190–302) are
significantly closer to the active site in the renin structures compared to those of endothiapepsininhibitor
complexes. This is partly due to a difference in relative position of the rigid body comprising
the C-domain. For instance, there is a domain rotation of ~4 ° and translation of ~0.1 Å in the human
renin complex with respect to the endothiapepsin-difluorostatone complex.
The entrance to the active-site cleft is made even narrower in renins as a consequence of differences in
the positions and composition of several well-defined loops and secondary structure elements. Unique to
the renins is a cis proline, Pro111, which caps a helix (h N2) and contributes to the subsites S 3 and
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