4dvf: Difference between revisions
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==Crystal structure of BACE1 with its inhibitor== | ==Crystal structure of BACE1 with its inhibitor== | ||
<StructureSection load='4dvf' size='340' side='right' caption='[[4dvf]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='4dvf' size='340' side='right'caption='[[4dvf]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4dvf]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4dvf]] is a 4 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=4DVF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DVF FirstGlance]. <br> | ||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PLJ:METHYL+L-PROLINATE'>PLJ</scene>, <scene name='pdbligand=PSA:3-HYDROXY-4-AMINO-5-PHENYLPENTANOIC+ACID'>PSA</scene>, <scene name='pdbligand=QSC:(1R)-1-PHENYLETHANAMINE'>QSC</scene>, <scene name='pdbligand=USC:5-[(METHYLSULFONYL)AMINO]BENZENE-1,3-DICARBOXYLIC+ACID'>USC</scene>, <scene name='pdbligand=ZAE:N-METHYL-D-PHENYLALANINE'>ZAE</scene></td></tr> | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PLJ:METHYL+L-PROLINATE'>PLJ</scene>, <scene name='pdbligand=PSA:3-HYDROXY-4-AMINO-5-PHENYLPENTANOIC+ACID'>PSA</scene>, <scene name='pdbligand=QSC:(1R)-1-PHENYLETHANAMINE'>QSC</scene>, <scene name='pdbligand=USC:5-[(METHYLSULFONYL)AMINO]BENZENE-1,3-DICARBOXYLIC+ACID'>USC</scene>, <scene name='pdbligand=ZAE:N-METHYL-D-PHENYLALANINE'>ZAE</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3uqp|3uqp]], [[3uqr|3uqr]], [[3uqu|3uqu]], [[3uqw|3uqw]], [[3uqx|3uqx]], [[4dv9|4dv9]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3uqp|3uqp]], [[3uqr|3uqr]], [[3uqu|3uqu]], [[3uqw|3uqw]], [[3uqx|3uqx]], [[4dv9|4dv9]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1 ([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=4dvf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dvf OCA], [https://pdbe.org/4dvf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dvf RCSB], [https://www.ebi.ac.uk/pdbsum/4dvf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dvf 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: Chen, T T]] | [[Category: Chen, T T]] | ||
Revision as of 12:31, 15 September 2021
Crystal structure of BACE1 with its inhibitorCrystal structure of BACE1 with its inhibitor
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 PubMedInspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPPbeta), membrane bound carboxyl terminal fragment (CTF), levels of beta-amyloid (Abeta) peptides and selectivity for beta-secretase (BACE1) over gamma-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Abeta levels in the rodent brain. Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases.,Liu Y, Zhang W, Li L, Salvador LA, Chen T, Chen W, Felsenstein KM, Ladd TB, Price AR, Golde TE, He J, Xu Y, Li Y, Luesch H J Med Chem. 2012 Dec 13;55(23):10749-65. doi: 10.1021/jm301630s. Epub 2012 Nov, 26. PMID:23181502[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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