2fdp: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2fdp]] is a 3 chain structure with 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]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FDP FirstGlance]. <br> | <table><tr><td colspan='2'>[[2fdp]] is a 3 chain structure with 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]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FDP FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr> | ||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><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.rcsb.org/pdb/explore.do?structureId=2fdp RCSB], [http://www.ebi.ac.uk/pdbsum/2fdp PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><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.rcsb.org/pdb/explore.do?structureId=2fdp RCSB], [http://www.ebi.ac.uk/pdbsum/2fdp PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Ballinger, M D | [[Category: Ballinger, M D]] | ||
[[Category: Fucini, R V | [[Category: Fucini, R V]] | ||
[[Category: Gordon, E M | [[Category: Gordon, E M]] | ||
[[Category: Jacobs, J W | [[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 S | [[Category: McDowell, R S]] | ||
[[Category: Randal, M | [[Category: Randal, M]] | ||
[[Category: Shi, X P | [[Category: Shi, X P]] | ||
[[Category: Sun, J | [[Category: Sun, J]] | ||
[[Category: Thomas, A E | [[Category: Thomas, A E]] | ||
[[Category: Wilkinson, J M | [[Category: Wilkinson, J M]] | ||
[[Category: Yang, W | [[Category: Yang, W]] | ||
[[Category: Zhong, M | [[Category: Zhong, M]] | ||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Bace]] | [[Category: Bace]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Revision as of 01:07, 25 December 2014
Crystal structure of beta-secretase complexed with an amino-ethylene inhibitorCrystal structure of beta-secretase complexed with an amino-ethylene inhibitor
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA 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. 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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