Inhibition of aspartic proteinases by transition state substrate analogs. X-ray studies of the complex of endothiapepsin with the renin inhibitor H-142

Hallett, Allan; Jones, D.; Atrash, Butrus; Szelke, M.; Leckie, Brenda J.; Beattie, S.R.; Dunn, B. M.; Valler, Martin J.; Rolph, Carole E.; Kay, John; Foundling, S.; Wood, S.P.; Pearl, Laurence H.; Watson, F.E.; Blundell, T.L.

doi:10.1515/9783111649788-041

Cited by 10 publications

(2 citation statements)

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“…Pepstatin derivatives such as lactoyl-pepstatin have Ki values ranging from 4 x 10-10 to 6 x 10-6 M towards human pepsin and gastricsin respectively (Valler et al, 1985a). Similarly, synthetic peptide inhibitors of renin containing statine (Boger et al, 1983) or other non-hydrolysable analogues (Szelke et al, 1982;Hallett et al, 1985), although they do display very effective inhibition of human renin (Ki values approx. 10-9-010 M), nevertheless demonstrate weaker interactions (approx.…”

Section: Methodsmentioning

confidence: 99%

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The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Dreyer¹,

Valler²,

Kay³

et al. 1985

Biochemical Journal

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The ability of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae) to affect the activities of a range of mammalian and microbial aspartic proteinases was examined. The inhibitor appeared to be completely selective in that only the aspartic proteinase A from yeast was inhibited to any significant extent. IA3 thus represents the first example of a totally specific, naturally occurring, aspartic-proteinase inhibitor.

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Section: Methodsmentioning

confidence: 99%

“…10-9-010 M), nevertheless demonstrate weaker interactions (approx. 10-8 M) with other aspartic proteinases such as Endothia parasitica proteinase (Hallett et al, 1985). In addition, the inhibitor peptide derived from the pro-part ofpepsinogen has also been shown to display preferential, but not exclusive, inhibition characteristics .…”

Section: Methodsmentioning

confidence: 99%

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Dreyer¹,

Valler²,

Kay³

et al. 1985

Biochemical Journal

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Renin inhibitors

Greenlee

1990

Medicinal Research Reviews

284

139

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Since the early 1980s, an intensive effort has been focused on the development of orally effective and long-acting inhibitors of renin. During this time, in vitro potency has increased greatly, with several transition-state inhibitor designs yielding inhibitors with subnanomolar IC50 values. In the meantime, both the molecular weight and peptide character of the inhibitors has decreased as important binding elements have been focused into smaller and more stable structures. The resulting inhibitors have shown promising activities in several in vivo models and (in two cases) in man. Nevertheless, renin inhibitors reported to date have limited oral bioavailability and short duration of action, and improvements in both will be necessary for them to compete effectively with ACE inhibitors. Renin inhibitors which have entered clinical studies have at least one naturally occurring amino acid and three or more amide bonds. It is reasonable to expect that continued development will produce wholly nonpeptide inhibitors with still lower MW, and it may be these "second-generation" inhibitors which will succeed as therapeutic agents. Development of orally effective and long-acting inhibitors of renin will enable their long-term antihypertensive efficacy and possible advantages over ACE inhibitor to be investigated.

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Domain flexibility in aspartic proteinases

et al. 1992

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Comparison of the three-dimensional structures of native endothiapepsin (EC 3.4.23.6) and 15 endothiapepsin oligopeptide inhibitor complexes defined at high resolution by X-ray crystallography shows that endothiapepsin exists in two forms differing in the relative orientation of a domain comprising residues 190-302. There are relatively few interactions between the two parts of the enzyme; consequently, they can move as separate rigid bodies. A translational, librational, and screw analysis of the thermal parameters of endothiapepsin also supports a model in which the two parts can move relative to each other. In the comparison of different aspartic proteinases, the rms values are reduced by up to 47% when the two parts of the structure are superposed independently. This justifies description of the differences, including those between pepsinogen and pepsin (EC 3.4.34.1), as a rigid movement of one part relative to another although considerable distortions within the domains also occur. The consequence of the rigid body movement is a change in the shape of the active site cleft that is largest around the S3 pocket. This is associated with a different position and conformation of the inhibitors that are bound to the two endothiapepsin forms. The relevance of these observations to a model of the hydrolysis by aspartic proteinases is briefly discussed.

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Inhibition of aspartic proteinases by transition state substrate analogs. X-ray studies of the complex of endothiapepsin with the renin inhibitor H-142

Cited by 10 publications

References 0 publications

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

The selectivity of action of the aspartic-proteinase inhibitor IA3 from yeast (Saccharomyces cerevisiae)

Renin inhibitors

Domain flexibility in aspartic proteinases

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