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2fdp
From Proteopedia
(New page: 200px<br /> <applet load="2fdp" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fdp, resolution 2.500Å" /> '''Crystal structure ...) |
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| - | [[Image:2fdp.gif|left|200px]]<br /> | + | [[Image:2fdp.gif|left|200px]]<br /><applet load="2fdp" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2fdp" size=" | + | |
caption="2fdp, resolution 2.500Å" /> | caption="2fdp, resolution 2.500Å" /> | ||
'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''<br /> | '''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | A series of novel beta-site amyloid precursor protein cleaving enzyme | + | A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 2FDP 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 FRP 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:// | + | 2FDP 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=FRP:'>FRP</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=2FDP OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Ballinger, M | + | [[Category: Ballinger, M D.]] |
| - | [[Category: Fucini, R | + | [[Category: Fucini, R V.]] |
| - | [[Category: Gordon, E | + | [[Category: Gordon, E M.]] |
| - | [[Category: Jacobs, J | + | [[Category: Jacobs, J W.]] |
[[Category: Lam, M.]] | [[Category: Lam, M.]] | ||
[[Category: Lu, W.]] | [[Category: Lu, W.]] | ||
[[Category: Lu, Y.]] | [[Category: Lu, Y.]] | ||
| - | [[Category: McDowell, R | + | [[Category: McDowell, R S.]] |
[[Category: Randal, M.]] | [[Category: Randal, M.]] | ||
| - | [[Category: Shi, X | + | [[Category: Shi, X P.]] |
[[Category: Sun, J.]] | [[Category: Sun, J.]] | ||
| - | [[Category: Thomas, A | + | [[Category: Thomas, A E.]] |
| - | [[Category: Wilkinson, J | + | [[Category: Wilkinson, J M.]] |
[[Category: Yang, W.]] | [[Category: Yang, W.]] | ||
[[Category: Zhong, M.]] | [[Category: Zhong, M.]] | ||
| Line 34: | Line 33: | ||
[[Category: bace]] | [[Category: bace]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:20:18 2008'' |
Revision as of 15:20, 21 February 2008
|
Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor
Overview
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
About this Structure
2FDP 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
Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1., Yang W, Lu W, Lu Y, Zhong M, Sun J, Thomas AE, Wilkinson JM, Fucini RV, Lam M, Randal M, Shi XP, Jacobs JW, McDowell RS, Gordon EM, Ballinger MD, J Med Chem. 2006 Feb 9;49(3):839-42. PMID:16451048
Page seeded by OCA on Thu Feb 21 17:20:18 2008
Categories: Homo sapiens | Memapsin 2 | Single protein | Ballinger, M D. | Fucini, R V. | Gordon, E M. | Jacobs, J W. | Lam, M. | Lu, W. | Lu, Y. | McDowell, R S. | Randal, M. | Shi, X P. | Sun, J. | Thomas, A E. | Wilkinson, J M. | Yang, W. | Zhong, M. | FRP | Aspartyl protease | Bace
