Modification of the interaction of human renin with different substrates by monoclonal antibodies.
The mechanism by which anti-renin antibody inhibits renin activity was studied by following the kinetics of the reaction with angiotensinogen or a low molecular weight synthetic substrate, tetradecapeptide (TDP). Two monoclonal antibodies (70 pM) inhibited the production of angiotensin I from angiotensinogen but they differed when hog TDP was used as a substrate. R3-47-10 partially and non-competitively inhibited, whereas R3-36-16 stimulated the activity of renin. This is in contrast to the effects of the synthetic renin inhibitor, CGP 29 287, which competitively inhibits the enzyme activity with both substrates. These antibodies probably bind to the renin molecule on the flap which protects the active cleft. Angiotensinogen may be prevented from entering the cleft due to steric hindrance from bound antibody. However TDP, because of its smaller size may still be able to reach the catalytic site. In addition R3-36-16 might freeze the flap in an open position allowing a greater turnover of TDP whereas R3-47-10 may prevent the flap from fully opening and thereby hinder the reaction of TDP with the active site.
de Gasparo
M
M
Biological Research Department, CIBA-GEIGY Ltd. Basle, Switzerland.
Wood
J M
JM
Heusser
C
C
D000808:Angiotensinogen / Q000031:analogs & derivatives / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001665:Binding Sites; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D012083:Renin / Q000276:immunology / Q000378:metabolism*; D013379:Substrate Specificity
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D000808:Angiotensinogen; D012083:Renin