2fdp

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[[Image:2fdp.gif|left|200px]]<br /><applet load="2fdp" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2fdp.gif|left|200px]]
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caption="2fdp, resolution 2.500&Aring;" />
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'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''<br />
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{{Structure
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|PDB= 2fdp |SIZE=350|CAPTION= <scene name='initialview01'>2fdp</scene>, resolution 2.500&Aring;
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|SITE=
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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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|ACTIVITY= [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]
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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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'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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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].
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2FDP is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FDP OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16451048 16451048]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/16451048 16451048]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]
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[[Category: bace]]
[[Category: bace]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:20:18 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:51:10 2008''

Revision as of 14:51, 20 March 2008

Image:2fdp.gif


PDB ID 2fdp

Drag the structure with the mouse to rotate
, resolution 2.500Å
Ligands:
Gene: BACE1 (Homo sapiens)
Activity: Memapsin 2, with EC number 3.4.23.46
Coordinates: save as pdb, mmCIF, xml



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

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