2v10: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2v10.gif|left|200px]]<br /><applet load="2v10" size=" | [[Image:2v10.gif|left|200px]]<br /><applet load="2v10" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2v10, resolution 3.1Å" /> | caption="2v10, resolution 3.1Å" /> | ||
'''CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9'''<br /> | '''CRYSTAL STRUCTURE OF RENIN WITH INHIBITOR 9'''<br /> | ||
| Line 5: | Line 5: | ||
==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== | ||
2V10 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with C61 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:C61 Binding Site For Chain O'>AC1</scene>. Full crystallographic information is available from [http:// | 2V10 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=C61:'>C61</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:C61 Binding Site For Chain O'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V10 OCA]. | ||
==Reference== | ==Reference== | ||
| Line 40: | Line 37: | ||
[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:42:00 2008'' | ||