3vg1: Difference between revisions

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-[[Image:3vg1.jpg|left|200px]]
+==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]] 1.77&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3vg1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [http://oca.weizmann.ac.il/oca-docs/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>
+<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='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 Homo sapiens])</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=3vg1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vg1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3vg1 RCSB], [http://www.ebi.ac.uk/pdbsum/3vg1 PDBsum]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Structure-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 &gt;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.
-{{STRUCTURE_3vg1|  PDB=3vg1  |  SCENE=  }}
+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<ref>PMID:22380629</ref>
-===Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experiment===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_22380629}}
+==See Also==
+*[[Beta secretase|Beta secretase]]
-==About this Structure==
+== References ==
-[[3vg1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VG1 OCA].
+<references/>
+__TOC__
-==Reference==
+</StructureSection>
-<ref group="xtra">PMID:021388807</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
 [[Category: Memapsin 2]]
-[[Category: Bourgier, E.]]
+[[Category: Bourgier, E]]
-[[Category: Rondeau, J M.]]
+[[Category: Rondeau, J M]]
 [[Category: Alzheimer's disease]]
 [[Category: Aspartic proteinase]]