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Figure 1
The three-dimensional structures of human (left) and mouse renins (right) showing
oligopeptide inhibitors bound in the active site cleft. The cleft lies between the N- and
C-terminal domains of the enzyme and is approximately perpendicular to the plane
of the page. It can accommodate 9–10 residues with the substrate/inhibitor bound
in an extended conformation. The catalytic aspartic acid residues (not shown)
are centrally placed at the base of the cleft.
Page 322
Renin is a member of the homologous group of enzymes known as aspartic proteinases that includes
pepsin and a group of fungal enzymes such as endothiapepsin, penicillopepsin, and rhizopuspepsin.
Their sequences all contain two aspartates (at positions 32 and 215 in porcine pepsin) that are essential
for catalytic activity. The crystal structures of several aspartic proteinases have been solved by x-ray
diffraction at high resolution, revealing a common bilobal structure with a large cleft between the N- and
C-terminal domains that can accommodate up to nine residues of a substrate (Figure 1) [3]. The two
essential carboxyls of Asp 32 and Asp 215 are within hydrogen-bonding distance and are approximately
co-planar due to the constraints of a hydrogen-bonding network involving residues of the two highly
conserved loops that contain the essential aspartates. The three-dimensional structures of the two
domains are related by a topological two-fold axis passing between the catalytic residues where the
pseudosymmetry happens to be strongest. Modeling studies based on the homology with other aspartic
proteinases showed that human renin assumes a tertiary structure that is similar to the other enzymes and
that the homology is greatest for the binding cleft region [4]. Subsequent x-ray analysis of the structure
of renin (described later) revealed the specific interactions made with inhibitors and implicated certain
loop regions covering the active site as being important for tight binding of peptides.
One enigmatic feature of renin is its extreme substrate specificity, its only known natural substrate being
a single Leu-Val peptide bond of angiotensinogen. The minimal synthetic analog is the 6–13 octapeptide
that encompasses the scissile peptide bond of angiotensinogen between residues 10 and 11 [5]. It has
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