2fdp: Difference between revisions
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New page: left|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== | ||
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[[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.]] | ||
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[[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'' | ||
