Mechanism of inhibition of human renin by monoclonal antibodies.
The mechanism by which monoclonal antibodies directed against human renin (R3-36-16 and R3-47-10) inhibit renin activity was investigated using various substrates. Both antibodies acted as potent inhibitors of human renin activity when human angiotensinogen was used as a substrate. However, their effects differed clearly in the presence of synthetic tetradecapeptide. When low concentrations of tetradecapeptide were used as substrate, renin activity was only partially inhibited by R3-47-10, whereas it was stimulated by R3-36-16. At higher synthetic substrate concentrations, both antibodies stimulated angiotensin I production. This effect was independent of the pH. Both antibodies exerted their effects in the presence of CGP 29287, a peptidic transition-state competitive renin inhibitor, indicating that their binding sites differed from that of CGP 29287. In combination, the stimulatory effect of R3-36-16 was not blocked by R3-47-10, but the inhibition produced by R3-47-10 was reversed by R3-36-16. Both antibodies may prevent the large natural substrate angiotensinogen from entering the enzymatic cleft by steric hindrance. At a low substrate concentration, R3-47-10 may also partially hinder the access of synthetic tetradecapeptide into the active cleft by steric hindrance. In contrast, the stimulating effect of both antibodies may be due to a conformational change in the renin molecule, allowing an increased access of tetradecapeptide or a more rapid release of the product from the enzymatic cleft.
de Gasparo
M M
MM
Research Department, CIBA-Geigy Limited, Basel, Switzerland.
Wood
J M
JM
Heusser
C H
CH
D000808:Angiotensinogen; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001666:Binding Sites, Antibody; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D051379:Mice; D009842:Oligopeptides; D012083:Renin / Q000494:pharmacology; D013379:Substrate Specificity; D013552:Swine; D000092502:Renin Inhibitors
D000808:Angiotensinogen; D000911:Antibodies, Monoclonal; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C045501:CGP 29287