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5t1w

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Current revision (15:35, 6 March 2024) (edit) (undo)
 
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<StructureSection load='5t1w' size='340' side='right'caption='[[5t1w]], [[Resolution|resolution]] 2.96&Aring;' scene=''>
<StructureSection load='5t1w' size='340' side='right'caption='[[5t1w]], [[Resolution|resolution]] 2.96&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5t1w]] 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=5T1W OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5T1W FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5t1w]] 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=5T1W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T1W FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=74B:(4AR,6R,8AS)-8A-(2,4-DIFLUORO-5-{[(2,2,2-TRIFLUOROETHYL)AMINO]METHYL}PHENYL)-6-(FLUOROMETHYL)-4,4A,5,6,8,8A-HEXAHYDROPYRANO[3,4-D][1,3]THIAZIN-2-AMINE'>74B</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.96&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5t1u|5t1u]]</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=74B:(4AR,6R,8AS)-8A-(2,4-DIFLUORO-5-{[(2,2,2-TRIFLUOROETHYL)AMINO]METHYL}PHENYL)-6-(FLUOROMETHYL)-4,4A,5,6,8,8A-HEXAHYDROPYRANO[3,4-D][1,3]THIAZIN-2-AMINE'>74B</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5t1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1w OCA], [https://pdbe.org/5t1w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t1w RCSB], [https://www.ebi.ac.uk/pdbsum/5t1w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1w ProSAT]</span></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'>[http://proteopedia.org/fgij/fg.htm?mol=5t1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1w OCA], [http://pdbe.org/5t1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t1w RCSB], [http://www.ebi.ac.uk/pdbsum/5t1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1w 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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A growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.
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Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.,Butler CR, Ogilvie K, Martinez-Alsina L, Barreiro G, Beck EM, Nolan CE, Atchison K, Benvenuti E, Buzon L, Doran S, Gonzales C, Helal CJ, Hou X, Hsu MH, Johnson EF, Lapham K, Lanyon L, Parris K, O'Neill BT, Riddell D, Robshaw A, Vajdos F, Brodney MA J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub, 2016 Dec 20. PMID:27997172<ref>PMID:27997172</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 5t1w" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Memapsin 2]]
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[[Category: Parris KD]]
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[[Category: Parris, K D]]
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[[Category: Vajdos F]]
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[[Category: Vajdos, F]]
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[[Category: Alzheimerss']]
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[[Category: Beta secretase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Inhibitor]]
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Current revision

Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

PDB ID 5t1w

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