Energy calculations on aspartic proteinases: human renin, endothiapepsin and its complex with an angiotensinogen fragment analogue, H-142.

The rational design of inhibitors of human renin for the treatment of hypertension depends on a detailed knowledge of the renin-angiotensinogen transition-state complex. Direct determination of the three-dimensional structure of complexes of human renin with transition state analogues is not possible until large quantities of human renin are made available by recombinant DNA techniques. Nevertheless, the sequence of the cDNA (Imai et al., 1983; Soubrier et al., 1983; Hardmann et al., 1984) and genomic DNA (Hobart et al., 1984) shows that human renin is closely homologous to other aspartic proteinases of both microbial and mammalian origins. Thus it has been possible to use the known sequences of more than ten aspartic proteinases (Tang, 1977; Kostka, 1985) and the three-dimensional structures of endothiapepsin (Pearl & Blundell, 1984), penicillopepsin (James & Sielecki, 1983), rhizopuspepsin (Bott et al., 1982) and porcine pepsin (Andreeva et al., 1984) as a guide to regions conserved in the primary, secondary and tertiary structures. These regions have been conserved in an interactive computer graphics modelling of mouse and human renins on the basis of the structure of endothiapepsin (Blundell et al., 1983; Sibanda el al., 1984). Fortunately, endothiapepsin has very low K , for substrates of human renin and this is reflected in its high affinity for inhibitors with the angiotensinogen sequence but with a modified scissile bond (e.g. -CH2NH=R) (Szelke et al., 1982; Hallett et al., 1985). Several of these have been co-crystallized with endothiapepsin and the structure of the complex between endothiapepsin and H-142 (I) has been defined by X-ray analysis (Hallett et al., 1985).