2v10

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{{STRUCTURE_2v10| PDB=2v10 | SCENE= }}
{{STRUCTURE_2v10| PDB=2v10 | SCENE= }}
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'''CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9'''
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===CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9===
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==Overview==
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BACKGROUND: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS: Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.
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(as it appears on PubMed at http://www.pubmed.gov), where 10903938 is the PubMed ID number.
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{{ABSTRACT_PUBMED_10903938}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin., Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG, Chem Biol. 2000 Jul;7(7):493-504. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10903938 10903938]
Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin., Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG, Chem Biol. 2000 Jul;7(7):493-504. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10903938 10903938]
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The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor., Rahuel J, Priestle JP, Grutter MG, J Struct Biol. 1991 Dec;107(3):227-36. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/1807356 1807356]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Renin]]
[[Category: Renin]]
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[[Category: Protease]]
[[Category: Protease]]
[[Category: Zymogen]]
[[Category: Zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:00:10 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 23:47:37 2008''

Revision as of 20:47, 28 July 2008

Image:2v10.png

Template:STRUCTURE 2v10

CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9

Template:ABSTRACT PUBMED 10903938

About this Structure

2V10 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin., Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG, Chem Biol. 2000 Jul;7(7):493-504. PMID:10903938

The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor., Rahuel J, Priestle JP, Grutter MG, J Struct Biol. 1991 Dec;107(3):227-36. PMID:1807356

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