2v10: Difference between revisions
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|SITE= <scene name='pdbsite=AC1:C61+Binding+Site+For+Chain+O'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:C61+Binding+Site+For+Chain+O'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=C61:(2R,4S,5S,7S)-5-AMINO-N-BUTYL-4-HYDROXY-7-[4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL]-2,8-DIMETHYLNONANAMIDE'>C61</scene> | |LIGAND= <scene name='pdbligand=C61:(2R,4S,5S,7S)-5-AMINO-N-BUTYL-4-HYDROXY-7-[4-METHOXY-3-(3-METHOXYPROPOXY)BENZYL]-2,8-DIMETHYLNONANAMIDE'>C61</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2v10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v10 OCA], [http://www.ebi.ac.uk/pdbsum/2v10 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2v10 RCSB]</span> | |||
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==Overview== | ==Overview== | ||
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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Stutz, S.]] | [[Category: Stutz, S.]] | ||
[[Category: Wood, J M.]] | [[Category: Wood, J M.]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
[[Category: aspartyl protease]] | [[Category: aspartyl protease]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:07:14 2008'' | ||
Revision as of 05:07, 31 March 2008
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| , resolution 3.1Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | |||||||
| Activity: | Renin, with EC number 3.4.23.15 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9
OverviewOverview
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.
About this StructureAbout this Structure
2V10 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Renin
- Single protein
- Cohen, N C.
- Cumin, F.
- Fuhrer, W.
- Goschke, R.
- Grutter, M G.
- Maibaum, J.
- Rahuel, J.
- Rasetti, V.
- Rueger, H.
- Stutz, S.
- Wood, J M.
- Alternative splicing
- Aspartyl protease
- Cleavage on pair of basic residue
- Glycoprotein
- Hydrolase
- Hydrolase(acid proteinase)
- Inhibitor-complex
- Polymorphism
- Protease
- Zymogen