4r8y
From Proteopedia
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==BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyclopentylacetyl)pyrrolidin-3-yl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium== | ==BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyclopentylacetyl)pyrrolidin-3-yl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium== | ||
| - | <StructureSection load='4r8y' size='340' side='right' caption='[[4r8y]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4r8y' size='340' side='right'caption='[[4r8y]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[4r8y]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R8Y OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[4r8y]] is a 2 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=4R8Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R8Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3KO:(2E,5R)-5-(2-CYCLOHEXYLETHYL)-5-{[(3R)-1-(CYCLOPENTYLACETYL)PYRROLIDIN-3-YL]METHYL}-2-IMINO-3-METHYLIMIDAZOLIDIN-4-ONE'>3KO</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 1.9Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3KO:(2E,5R)-5-(2-CYCLOHEXYLETHYL)-5-{[(3R)-1-(CYCLOPENTYLACETYL)PYRROLIDIN-3-YL]METHYL}-2-IMINO-3-METHYLIMIDAZOLIDIN-4-ONE'>3KO</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=4r8y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r8y OCA], [https://pdbe.org/4r8y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r8y RCSB], [https://www.ebi.ac.uk/pdbsum/4r8y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r8y ProSAT]</span></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</table> | </table> | ||
| + | == 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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Abeta40 levels upon subcutaneous and oral administration to rats. | ||
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| + | Discovery of potent iminoheterocycle BACE1 inhibitors.,Caldwell JP, Mazzola RD, Durkin J, Chen J, Chen X, Favreau L, Kennedy M, Kuvelkar R, Lee J, McHugh N, McKittrick B, Orth P, Stamford A, Strickland C, Voigt J, Wang L, Zhang L, Zhang Q, Zhu Z Bioorg Med Chem Lett. 2014 Oct 23;24(23):5455-5459. doi:, 10.1016/j.bmcl.2014.10.006. PMID:25455483<ref>PMID:25455483</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 4r8y" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Caldwell JP]] |
| - | [[Category: | + | [[Category: Orth P]] |
| - | [[Category: | + | [[Category: Strickland C]] |
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Current revision
BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyclopentylacetyl)pyrrolidin-3-yl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium
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