View source for 1fq7

[[Image:1fq7.jpg|left|200px]]<br /><applet load="1fq7" size="350" color="white" frame="true" align="right" spinBox="true" 
caption="1fq7, resolution 2.8&Aring;" />
'''X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN'''<br />

==Overview==
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.

==About this Structure==
1FQ7 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=NAG:'>NAG</scene>, <scene name='pdbligand=BOC:'>BOC</scene>, <scene name='pdbligand=PHE:'>PHE</scene>, <scene name='pdbligand=HIS:'>HIS</scene>, <scene name='pdbligand=CAL:'>CAL</scene> and <scene name='pdbligand=NME:'>NME</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=1FQ7 OCA]. 

==Reference==
X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity., Cronin NB, Badasso MO, J Tickle I, Dreyer T, Hoover DJ, Rosati RL, Humblet CC, Lunney EA, Cooper JB, J Mol Biol. 2000 Nov 10;303(5):745-60. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11061973 11061973]
[[Category: Saccharomyces cerevisiae]]
[[Category: Saccharopepsin]]
[[Category: Single protein]]
[[Category: Badasso, M O.]]
[[Category: Cooper, J B.]]
[[Category: Cronin, N B.]]
[[Category: Dreyer, T.]]
[[Category: Hoover, D J.]]
[[Category: Humblet, C C.]]
[[Category: Lunney, E A.]]
[[Category: Rosati, R L.]]
[[Category: Tickle, I J.]]
[[Category: BOC]]
[[Category: CAL]]
[[Category: HIS]]
[[Category: NAG]]
[[Category: NME]]
[[Category: PHE]]
[[Category: hydrophobic inhibitor]]
[[Category: t-boc terminal group]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:41:26 2008''