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| {{STRUCTURE_1fq7| PDB=1fq7 | SCENE= }} | | {{STRUCTURE_1fq7| PDB=1fq7 | SCENE= }} |
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| '''X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN'''
| | ===X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN=== |
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| ==Overview==
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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 A resolution. This inhibitor has low affinity for human renin yet binds very tightly to the yeast proteinase (K(i)=4 nM). The high affinity of this inhibitor can be attributed to its bulky cyclic moiety spanning P(2)-P(3)' 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 A resolution structure of the complex with CP-108,420 shows that its benzimidazole P(3 )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 P(2), has a high affinity for renin (K(i)=5 nM) but proves to be a poor inhibitor for saccharopepsin (K(i)=3.7 microM). This may stem from the fact that the histidine residue would not bind favourably with the predominantly hydrophobic S(2) sub-site of saccharopepsin.
| | The line below this paragraph, {{ABSTRACT_PUBMED_11061973}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 11061973 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_11061973}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Hydrophobic inhibitor]] | | [[Category: Hydrophobic inhibitor]] |
| [[Category: T-boc terminal group]] | | [[Category: T-boc terminal group]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 16:38:07 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 03:46:31 2008'' |