4d83: Difference between revisions
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==Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a co-crystallization experiment== | ==Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a co-crystallization experiment== | ||
<StructureSection load='4d83' size='340' side='right' caption='[[4d83]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='4d83' size='340' side='right'caption='[[4d83]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4d83]] is a 3 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4d83]] 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=4D83 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D83 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0GT:(3R,4S,5S)-3-[(3-TERT-BUTYLBENZYL)AMINO]-5-{[3-(2,2-DIFLUOROETHYL)-1H-INDOL-5-YL]METHYL}TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>0GT</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0GT:(3R,4S,5S)-3-[(3-TERT-BUTYLBENZYL)AMINO]-5-{[3-(2,2-DIFLUOROETHYL)-1H-INDOL-5-YL]METHYL}TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>0GT</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=4d83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d83 OCA], [https://pdbe.org/4d83 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d83 RCSB], [https://www.ebi.ac.uk/pdbsum/4d83 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d83 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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 == | ||
| Line 21: | Line 18: | ||
</div> | </div> | ||
<div class="pdbe-citations 4d83" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4d83" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bourgier | [[Category: Bourgier E]] | ||
[[Category: Rondeau | [[Category: Rondeau JM]] | ||
Revision as of 10:52, 14 September 2022
Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a co-crystallization experimentCrystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a co-crystallization experiment
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] Publication Abstract from PubMedStructure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 mumol/kg demonstrated significant reduction of brain Abeta levels. Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid beta-peptides.,Rueeger H, Lueoend R, Rogel O, Rondeau JM, Mobitz H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S, Neumann U J Med Chem. 2012 Apr 12;55(7):3364-86. Epub 2012 Mar 21. PMID:22380629[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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