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1fq7
From Proteopedia
(New page: 200px<br /><applet load="1fq7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fq7, resolution 2.8Å" /> '''X-RAY STRUCTURE OF IN...) |
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| - | [[Image:1fq7.jpg|left|200px]]<br /><applet load="1fq7" size=" | + | [[Image:1fq7.jpg|left|200px]]<br /><applet load="1fq7" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1fq7, resolution 2.8Å" /> | caption="1fq7, resolution 2.8Å" /> | ||
'''X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN'''<br /> | '''X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Saccharopepsin is a vacuolar aspartic proteinase involved in activation of | + | 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== | ==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 NAG, BOC, PHE, HIS, CAL and NME 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:// | + | 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== | ==Reference== | ||
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[[Category: Saccharopepsin]] | [[Category: Saccharopepsin]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Badasso, M | + | [[Category: Badasso, M O.]] |
| - | [[Category: Cooper, J | + | [[Category: Cooper, J B.]] |
| - | [[Category: Cronin, N | + | [[Category: Cronin, N B.]] |
[[Category: Dreyer, T.]] | [[Category: Dreyer, T.]] | ||
| - | [[Category: Hoover, D | + | [[Category: Hoover, D J.]] |
| - | [[Category: Humblet, C | + | [[Category: Humblet, C C.]] |
| - | [[Category: Lunney, E | + | [[Category: Lunney, E A.]] |
| - | [[Category: Rosati, R | + | [[Category: Rosati, R L.]] |
| - | [[Category: Tickle, I | + | [[Category: Tickle, I J.]] |
[[Category: BOC]] | [[Category: BOC]] | ||
[[Category: CAL]] | [[Category: CAL]] | ||
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[[Category: t-boc terminal group]] | [[Category: t-boc terminal group]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:41:26 2008'' |
Revision as of 10:41, 21 February 2008
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X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN
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 Single protein structure of sequence from Saccharomyces cerevisiae with , , , , and as ligands. Active as Saccharopepsin, with EC number 3.4.23.25 Full crystallographic information is available from 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:11061973
Page seeded by OCA on Thu Feb 21 12:41:26 2008
Categories: Saccharomyces cerevisiae | Saccharopepsin | Single protein | Badasso, M O. | Cooper, J B. | Cronin, N B. | Dreyer, T. | Hoover, D J. | Humblet, C C. | Lunney, E A. | Rosati, R L. | Tickle, I J. | BOC | CAL | HIS | NAG | NME | PHE | Hydrophobic inhibitor | T-boc terminal group
