4zpe

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'''Unreleased structure'''
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==BACE1 in complex with 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one==
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<StructureSection load='4zpe' size='340' side='right' caption='[[4zpe]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4zpe]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZPE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZPE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4QA:4-(CYCLOHEXYLAMINO)-1-(3-FLUOROPHENYL)-8-[3-(PROPAN-2-YLOXY)BENZYL]-1,3,8-TRIAZASPIRO[4.5]DEC-3-EN-2-ONE'>4QA</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3fkt|3fkt]]</td></tr>
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<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>
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<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=4zpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zpe OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zpe RCSB], [http://www.ebi.ac.uk/pdbsum/4zpe PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
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The entry 4zpe is ON HOLD until Paper Publication
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Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.,Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL Bioorg Med Chem Lett. 2015 Jun 29. pii: S0960-894X(15)00687-3. doi:, 10.1016/j.bmcl.2015.06.082. PMID:26195137<ref>PMID:26195137</ref>
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Authors: Orth, P.
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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Description: BACE1 in complex with 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one
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== References ==
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[[Category: Unreleased Structures]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Memapsin 2]]
[[Category: Orth, P]]
[[Category: Orth, P]]
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[[Category: Alzheimer disease]]
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[[Category: Amyloid beta-peptide]]
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[[Category: Amyloid precursor protein secretase]]
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[[Category: Aspartic acid endopeptidase]]
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[[Category: Binding site]]
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[[Category: Drug design]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Model]]
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[[Category: Molecular]]
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[[Category: Protease inhibitor]]
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[[Category: Structure-activity relationship]]
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[[Category: Transgenic]]

Revision as of 20:03, 5 August 2015

BACE1 in complex with 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one

4zpe, resolution 1.70Å

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