4di2: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4di2]] is a 3 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=4DI2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DI2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4di2]] is a 3 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=4DI2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DI2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0K9:(2R)-N-{(2S,3R)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL]AMINO}-3-HYDROXY-1-[3-(1,3-THIAZOL-2-YL)PHENYL]BUTAN-2-YL}-2-METHOXYPROPANAMIDE'>0K9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0K9:(2R)-N-{(2S,3R)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL]AMINO}-3-HYDROXY-1-[3-(1,3-THIAZOL-2-YL)PHENYL]BUTAN-2-YL}-2-METHOXYPROPANAMIDE'>0K9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4di2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4di2 OCA], [https://pdbe.org/4di2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4di2 RCSB], [https://www.ebi.ac.uk/pdbsum/4di2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4di2 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4di2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4di2 OCA], [https://pdbe.org/4di2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4di2 RCSB], [https://www.ebi.ac.uk/pdbsum/4di2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4di2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[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> | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Latest revision as of 09:53, 27 November 2024
Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37
Structural highlights
FunctionBACE1_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] Publication Abstract from PubMedWe have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-beta peptide (Abeta) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Abeta levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1. Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.,Dineen TA, Weiss MM, Williamson T, Acton P, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dunn RT 2nd, Esmay J, Graceffa RF, Harried SS, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, San Miguel T, Sickmier EA, Vargas HM, Wahl RC, Wen PH, Whittington DA, Wood S, Xue Q, Yang BH, Patel VF, Zhong W J Med Chem. 2012 Apr 18. PMID:22468684[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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