3wb4: Difference between revisions
No edit summary |
No edit summary |
||
| Line 9: | Line 9: | ||
<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=3wb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wb4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wb4 RCSB], [http://www.ebi.ac.uk/pdbsum/3wb4 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=3wb4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wb4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wb4 RCSB], [http://www.ebi.ac.uk/pdbsum/3wb4 PDBsum]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[[http://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 == | ||
Revision as of 01:30, 26 December 2014
Crystal Structure of beta secetase in complex with 2-amino-3,6-dimethyl-6-(2-phenylethyl)-3,4,5,6-tetrahydropyrimidin-4-oneCrystal Structure of beta secetase in complex with 2-amino-3,6-dimethyl-6-(2-phenylethyl)-3,4,5,6-tetrahydropyrimidin-4-one
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 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||