X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity
Cronin, N.B., Badasso, M.O., Tickle, I.J., Dreyer, T., Hoover, D.J., Rosati, R.L., Humblet, C.C., Lunney, E.A. and Cooper, J.B. (2000) X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity. Journal of Molecular Biology, 303, (5), 745-760. (doi:10.1006/jmbi.2000.4181).
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Saccharopepsin is a vacuolar aspartic proteinase involved in activation of a number of hydrolases. The enzyme has great structural homology to mammalian aspartic proteinases including human renin and we have used it as a model system to study the binding of renin inhibitors by X-ray crystallography. Five medium-to-high resolution structures of saccharopepsin complexed with transition-state analogue renin inhibitors were determined. The structure of a cyclic peptide inhibitor (PD-129,541) complexed with the proteinase was solved to 2.5 Å resolution. This inhibitor has low affinity for human renin yet binds very tightly to the yeast proteinase (Ki=4 nM). The high affinity of this inhibitor can be attributed to its bulky cyclic moiety spanning P2-P3′ and other residues that appear to optimally fit the binding sub-sites of the enzyme. Superposition of the saccharopepsin structure on that of renin showed that a movement of the loop 286–301 relative to renin facilitates tighter binding of this inhibitor to saccharopepsin. Our 2.8 Å resolution structure of the complex with CP-108,420 shows that its benzimidazole P3 replacement retains one of the standard hydrogen bonds that normally involve the inhibitor’s main-chain. This suggests a non-peptide lead in overcoming the problem of susceptible peptide bonds in the design of aspartic proteinase inhibitors. CP-72,647 which possesses a basic histidine residue at P2, has a high affinity for renin (Ki=5 nM) but proves to be a poor inhibitor for saccharopepsin (Ki=3.7 μM). This may stem from the fact that the histidine residue would not bind favourably with the predominantly hydrophobic S2 sub-site of saccharopepsin.
|Keywords:||renin inhibitors, aspartic proteinases, saccharopepsin|
|Subjects:||R Medicine > R Medicine (General)
Q Science > QR Microbiology
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||22 Aug 2008|
|Last Modified:||12 May 2013 01:14|
|Contributors:||Cronin, N.B. (Author)
Badasso, M.O. (Author)
Tickle, I.J. (Author)
Dreyer, T. (Author)
Hoover, D.J. (Author)
Rosati, R.L. (Author)
Humblet, C.C. (Author)
Lunney, E.A. (Author)
Cooper, J.B. (Author)
|Date:||10 November 2000|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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