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==Crystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-one== | ==Crystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-one== | ||
<StructureSection load='3wb5' size='340' side='right' caption='[[3wb5]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='3wb5' size='340' side='right'caption='[[3wb5]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3wb5]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3wb5]] is a 1 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=3WB5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WB5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0B4:(6S)-2-AMINO-3,6-DIMETHYL-6-[(1R,2R)-2-PHENYLCYCLOPROPYL]-5,6-DIHYDROPYRIMIDIN-4(3H)-ONE'>0B4</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.501Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0B4:(6S)-2-AMINO-3,6-DIMETHYL-6-[(1R,2R)-2-PHENYLCYCLOPROPYL]-5,6-DIHYDROPYRIMIDIN-4(3H)-ONE'>0B4</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=3wb5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wb5 OCA], [https://pdbe.org/3wb5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wb5 RCSB], [https://www.ebi.ac.uk/pdbsum/3wb5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wb5 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 17: | ||
</div> | </div> | ||
<div class="pdbe-citations 3wb5" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3wb5" 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: Arisawa | [[Category: Arisawa M]] | ||
[[Category: Fujiwara | [[Category: Fujiwara K]] | ||
[[Category: Hattori | [[Category: Hattori K]] | ||
[[Category: Hosono | [[Category: Hosono M]] | ||
[[Category: Muto | [[Category: Muto C]] | ||
[[Category: Nakano | [[Category: Nakano T]] | ||
[[Category: Shuto | [[Category: Shuto S]] | ||
[[Category: Takemoto | [[Category: Takemoto H]] | ||
[[Category: Tanaka | [[Category: Tanaka Y]] | ||
[[Category: Yamakawa | [[Category: Yamakawa H]] | ||
[[Category: Yamamoto | [[Category: Yamamoto T]] | ||
[[Category: Yonezawa | [[Category: Yonezawa S]] | ||
Latest revision as of 05:36, 21 November 2024
Crystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-oneCrystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-one
Structural highlights
Publication Abstract from PubMedFor further investigation of BACE1 inhibitors using conformational restriction with sp3 hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be approximately 0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring. Conformational restriction approach to beta-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations.,Yonezawa S, Fujiwara K, Yamamoto T, Hattori K, Yamakawa H, Muto C, Hosono M, Tanaka Y, Nakano T, Takemoto H, Arisawa M, Shuto S Bioorg Med Chem. 2013 Aug 28. pii: S0968-0896(13)00730-X. doi:, 10.1016/j.bmc.2013.08.036. PMID:24051074[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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