2qmg

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[[Image:2qmg.jpg|left|200px]]
 
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{{Structure
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==Structure of BACE Bound to SCH745966==
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|PDB= 2qmg |SIZE=350|CAPTION= <scene name='initialview01'>2qmg</scene>, resolution 1.890&Aring;
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<StructureSection load='2qmg' size='340' side='right'caption='[[2qmg]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
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|SITE= <scene name='pdbsite=AC1:Sc6+Binding+Site+For+Residue+A+1'>AC1</scene>, <scene name='pdbsite=AC2:Sc6+Binding+Site+For+Residue+B+1'>AC2</scene>, <scene name='pdbsite=AC3:Tar+Binding+Site+For+Residue+A+2'>AC3</scene> and <scene name='pdbsite=AC4:Tar+Binding+Site+For+Residue+B+3'>AC4</scene>
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=SC6:N-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R,4R)-4-PHENOXYPYRROLIDIN-2-YL]ETHYL}-3-{[(2R)-2-(METHOXYMETHYL)PYRROLIDIN-1-YL]CARBONYL}-5-METHYLBENZAMIDE'>SC6</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene>
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<table><tr><td colspan='2'>[[2qmg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QMG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QMG FirstGlance]. <br>
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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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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.89&#8491;</td></tr>
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|GENE= BACE1, BACE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SC6:N-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R,4R)-4-PHENOXYPYRROLIDIN-2-YL]ETHYL}-3-{[(2R)-2-(METHOXYMETHYL)PYRROLIDIN-1-YL]CARBONYL}-5-METHYLBENZAMIDE'>SC6</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2qmg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qmg OCA], [https://pdbe.org/2qmg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qmg RCSB], [https://www.ebi.ac.uk/pdbsum/2qmg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qmg ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2qk5|2qk5]], [[2qkj|2qkj]], [[2qmd|2qmd]], [[2qmf|2qmf]], [[2qp8|2qp8]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qmg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qmg OCA], [http://www.ebi.ac.uk/pdbsum/2qmg PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qmg RCSB]</span>
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== Function ==
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}}
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[https://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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qm/2qmg_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qmg ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b. Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11. Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.
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'''Structure of BACE Bound to SCH745966'''
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Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor.,Iserloh U, Pan J, Stamford AW, Kennedy ME, Zhang Q, Zhang L, Parker EM, McHugh NA, Favreau L, Strickland C, Voigt J Bioorg Med Chem Lett. 2008 Jan 1;18(1):418-22. Epub 2007 Oct 18. PMID:17980584<ref>PMID:17980584</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2qmg" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b. Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11. Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2QMG 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=2QMG OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor., Iserloh U, Pan J, Stamford AW, Kennedy ME, Zhang Q, Zhang L, Parker EM, McHugh NA, Favreau L, Strickland C, Voigt J, Bioorg Med Chem Lett. 2008 Jan 1;18(1):418-22. Epub 2007 Oct 18. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17980584 17980584]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Memapsin 2]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Iserloh U]]
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[[Category: Iserloh, U.]]
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[[Category: Strickland CO]]
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[[Category: Strickland, C O.]]
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[[Category: alternative splicing]]
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[[Category: aspartyl protease]]
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[[Category: bace1]]
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[[Category: glycoprotein]]
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[[Category: hydrolase]]
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[[Category: membrane]]
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[[Category: protease]]
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[[Category: transmembrane]]
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[[Category: zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:50:54 2008''
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Current revision

Structure of BACE Bound to SCH745966

PDB ID 2qmg

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