4d89: Difference between revisions
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==Crystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a soaking experiment== | ==Crystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a soaking experiment== | ||
<StructureSection load='4d89' size='340' side='right' caption='[[4d89]], [[Resolution|resolution]] 1.65Å' scene=''> | <StructureSection load='4d89' size='340' side='right' caption='[[4d89]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4d89]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4d89]] 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=4D89 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D89 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BXD:(3S,4S,5R)-3-(4-AMINO-3-{[(2R)-3-ETHOXY-1,1,1-TRIFLUOROPROPAN-2-YL]OXY}-5-FLUOROBENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>BXD</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BXD:(3S,4S,5R)-3-(4-AMINO-3-{[(2R)-3-ETHOXY-1,1,1-TRIFLUOROPROPAN-2-YL]OXY}-5-FLUOROBENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>BXD</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3veu|3veu]], [[3vf3|3vf3]], [[3vg1|3vg1]], [[4d83|4d83]], [[4d85|4d85]], [[4d88|4d88]], [[4d8c|4d8c]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3veu|3veu]], [[3vf3|3vf3]], [[3vg1|3vg1]], [[4d83|4d83]], [[4d85|4d85]], [[4d88|4d88]], [[4d8c|4d8c]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<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> | <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> | ||
<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=4d89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d89 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d89 RCSB], [http://www.ebi.ac.uk/pdbsum/4d89 PDBsum]</span></td></tr> | <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=4d89 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d89 OCA], [http://pdbe.org/4d89 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d89 RCSB], [http://www.ebi.ac.uk/pdbsum/4d89 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d89 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4d89" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Bourgier, E]] | [[Category: Bourgier, E]] | ||
Revision as of 12:08, 4 August 2016
Crystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a soaking experimentCrystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a soaking 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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