5ie1

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==Crystal structure of BACE1 in complex with 3-(2-amino-6-(o-tolyl)quinolin-3-yl)-N-(3,3-dimethylbutyl)propanamide==
==Crystal structure of BACE1 in complex with 3-(2-amino-6-(o-tolyl)quinolin-3-yl)-N-(3,3-dimethylbutyl)propanamide==
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<StructureSection load='5ie1' size='340' side='right' caption='[[5ie1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='5ie1' size='340' side='right'caption='[[5ie1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ie1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IE1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IE1 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ie1]] is a 1 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=5IE1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IE1 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6BS:3-[2-AMINO-6-(2-METHYLPHENYL)QUINOLIN-3-YL]-N-(3,3-DIMETHYLBUTYL)PROPANAMIDE'>6BS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
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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]] 2.298&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6BS:3-[2-AMINO-6-(2-METHYLPHENYL)QUINOLIN-3-YL]-N-(3,3-DIMETHYLBUTYL)PROPANAMIDE'>6BS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
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<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>
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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=5ie1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ie1 OCA], [https://pdbe.org/5ie1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ie1 RCSB], [https://www.ebi.ac.uk/pdbsum/5ie1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ie1 ProSAT]</span></td></tr>
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<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=5ie1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ie1 OCA], [http://pdbe.org/5ie1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ie1 RCSB], [http://www.ebi.ac.uk/pdbsum/5ie1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ie1 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[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>
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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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, beta-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.
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Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase.,Jordan JB, Whittington DA, Bartberger MD, Sickmier EA, Chen K, Cheng Y, Judd T J Med Chem. 2016 Apr 28;59(8):3732-49. doi: 10.1021/acs.jmedchem.5b01917. Epub, 2016 Apr 6. PMID:26978477<ref>PMID:26978477</ref>
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==See Also==
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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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 5ie1" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Memapsin 2]]
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[[Category: Large Structures]]
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[[Category: Bartberger, M D]]
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[[Category: Bartberger MD]]
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[[Category: Chen, K]]
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[[Category: Chen K]]
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[[Category: Cheng, Y]]
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[[Category: Cheng Y]]
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[[Category: Jordan, J B]]
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[[Category: Jordan JB]]
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[[Category: Judd, T]]
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[[Category: Judd T]]
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[[Category: Sickmier, E A]]
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[[Category: Sickmier EA]]
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[[Category: Whittington, D A]]
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[[Category: Whittington DA]]
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[[Category: Alzheimer's disease]]
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[[Category: Amyloid precursor protein]]
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[[Category: App]]
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[[Category: Aspartic protease]]
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[[Category: Hydrolase]]
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Current revision

Crystal structure of BACE1 in complex with 3-(2-amino-6-(o-tolyl)quinolin-3-yl)-N-(3,3-dimethylbutyl)propanamide

PDB ID 5ie1

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