2fdp

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[[Image:2fdp.gif|left|200px]]
[[Image:2fdp.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2fdp |SIZE=350|CAPTION= <scene name='initialview01'>2fdp</scene>, resolution 2.500&Aring;
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The line below this paragraph, containing "STRUCTURE_2fdp", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=FRP:N1-((2S,3S,5R)-3-AMINO-6-(4-FLUOROPHENYLAMINO)-5-METHYL-6-OXO-1-PHENYLHEXAN-2-YL)-N3,N3-DIPROPYLISOPHTHALAMIDE'>FRP</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= BACE1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2fdp| PDB=2fdp | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2fdp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fdp OCA], [http://www.ebi.ac.uk/pdbsum/2fdp PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2fdp RCSB]</span>
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}}
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'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''
'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''
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[[Category: Yang, W.]]
[[Category: Yang, W.]]
[[Category: Zhong, M.]]
[[Category: Zhong, M.]]
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[[Category: aspartyl protease]]
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[[Category: Aspartyl protease]]
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[[Category: bace]]
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[[Category: Bace]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:46:24 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:01:21 2008''
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Revision as of 00:46, 4 May 2008

Image:2fdp.gif

Template:STRUCTURE 2fdp

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. 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 Sun May 4 03:46:24 2008

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