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).
Download
Full text not available from this repository.
Description/Abstract
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.
| Item Type: | Article |
|---|---|
| ISSNs: | 0022-2836 (print) |
| Related URLs: | |
| 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 |
| Item ID: | 56414 |
| 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 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/56414 |
Actions (login required)
 |
View Item |
