2f3e
From Proteopedia
(New page: 200px<br /> <applet load="2f3e" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f3e, resolution 2.110Å" /> '''Crystal Structure ...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2f3e.gif|left|200px]]<br /> | + | [[Image:2f3e.gif|left|200px]]<br /><applet load="2f3e" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2f3e" size=" | + | |
caption="2f3e, resolution 2.110Å" /> | caption="2f3e, resolution 2.110Å" /> | ||
'''Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor'''<br /> | '''Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide | + | Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions. |
==About this Structure== | ==About this Structure== | ||
| - | 2F3E 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 AXQ as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] Full crystallographic information is available from [http:// | + | 2F3E 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=AXQ:'>AXQ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F3E OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Rondeau, J | + | [[Category: Rondeau, J M.]] |
[[Category: AXQ]] | [[Category: AXQ]] | ||
[[Category: alzheimer's disease]] | [[Category: alzheimer's disease]] | ||
| Line 23: | Line 22: | ||
[[Category: memapsin2]] | [[Category: memapsin2]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:17 2008'' |
Revision as of 15:17, 21 February 2008
|
Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor
Overview
Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.
About this Structure
2F3E is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.
Reference
Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)., Hanessian S, Yang G, Rondeau JM, Neumann U, Betschart C, Tintelnot-Blomley M, J Med Chem. 2006 Jul 27;49(15):4544-67. PMID:16854060
Page seeded by OCA on Thu Feb 21 17:17:17 2008
