1FQ7

X-RAY STRUCTURE OF INHIBITOR CP-72,647 BOUND TO SACCHAROPEPSIN

Summary for 1FQ7

• Entry DOI: 10.2210/pdb1fq7/pdb
• Related: 1dp5 1fq4 1fq5 1fq6 1fq8 2jxr
• Related PRD ID: PRD_000564
• Descriptor: SACCHAROPEPSIN, beta-D-arabino-hexopyranos-2-ulose-(1-2)-beta-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, N-(tert-butoxycarbonyl)-L-phenylalanyl-N-[(2S,3S,5R)-1-cyclohexyl-3-hydroxy-7-methyl-5-(methylcarbamoyl)octan-2-yl]-L-histidinamide, ... (5 entities in total)
• Functional Keywords: hydrophobic inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (baker's yeast)
• Total number of polymer chains: 1
• Total formula weight: 37587.46

Authors

Cronin, N.B.,Badasso, M.O.,Tickle, I.J.,Dreyer, T.,Hoover, D.J.,Rosati, R.L.,Humblet, C.C.,Lunney, E.A.,Cooper, J.B. (deposition date: 2000-09-04, release date: 2000-09-20, Last modification date: 2024-11-20)

Primary citation

Cronin, N.B.,Badasso, M.O.,J Tickle, I.,Dreyer, T.,Hoover, D.J.,Rosati, R.L.,Humblet, C.C.,Lunney, E.A.,Cooper, J.B.
X-ray structures of five renin inhibitors bound to saccharopepsin: exploration of active-site specificity.
J.Mol.Biol., 303:745-760, 2000

PubMed 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 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.

PubMed: 11061973
DOI: 10.1006/jmbi.2000.4181

Experimental method

X-RAY DIFFRACTION (2.8 Å)