1fq5: Difference between revisions

[[Image:1fq5.jpg|left|200px]]<br /><applet load="1fq5" size="350" color="white" frame="true" align="right" spinBox="true"  

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.

1FQ5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with <scene name='pdbligand=NDG:'>NDG</scene>, <scene name='pdbligand=NPY:'>NPY</scene>, <scene name='pdbligand=NPD:'>NPD</scene>, <scene name='pdbligand=GLU:'>GLU</scene>, <scene name='pdbligand=STA:'>STA</scene>, <scene name='pdbligand=LEU:'>LEU</scene> and <scene name='pdbligand=TRJ:'>TRJ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Saccharopepsin Saccharopepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.25 3.4.23.25] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FQ5 OCA].  

[[Category: Badasso, M O.]]

[[Category: Cooper, J B.]]

[[Category: Cronin, N B.]]

[[Category: Hoover, D J.]]

[[Category: Humblet, C C.]]

[[Category: Lunney, E A.]]

[[Category: Rosati, R L.]]

[[Category: Tickle, I J.]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:41:25 2008''