3vg1: Difference between revisions
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==Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experiment== | ==Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experiment== | ||
<StructureSection load='3vg1' size='340' side='right' caption='[[3vg1]], [[Resolution|resolution]] 1.77Å' scene=''> | <StructureSection load='3vg1' size='340' side='right'caption='[[3vg1]], [[Resolution|resolution]] 1.77Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3vg1]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3vg1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VG1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VG1 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> | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3veu|3veu]], [[3vf3|3vf3]], [[4d89|4d89]], [[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"><div style='overflow: auto; max-height: 3em;'>[[3veu|3veu]], [[3vf3|3vf3]], [[4d89|4d89]], [[4d83|4d83]], [[4d85|4d85]], [[4d88|4d88]], [[4d8c|4d8c]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([https://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'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vg1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vg1 OCA], [https://pdbe.org/3vg1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vg1 RCSB], [https://www.ebi.ac.uk/pdbsum/3vg1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vg1 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 == | ||
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==See Also== | ==See Also== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Bourgier, E]] | [[Category: Bourgier, E]] | ||
Revision as of 21:43, 27 July 2022
Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experimentCrystal Structure of Human Beta Secretase in Complex with NVP-BUR436, 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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