4r91

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==BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium==
==BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium==
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<StructureSection load='4r91' size='340' side='right' caption='[[4r91]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
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<StructureSection load='4r91' size='340' side='right'caption='[[4r91]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4r91]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R91 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4r91]] 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=4R91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R91 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=3KT:(2E,5R)-5-(2-CYCLOHEXYLETHYL)-5-{[(1S,3R)-3-(CYCLOPENTYLAMINO)CYCLOHEXYL]METHYL}-2-IMINO-3-METHYLIMIDAZOLIDIN-4-ONE'>3KT</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4r8y|4r8y]], [[4r92|4r92]], [[4r93|4r93]], [[4r95|4r95]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3KT:(2E,5R)-5-(2-CYCLOHEXYLETHYL)-5-{[(1S,3R)-3-(CYCLOPENTYLAMINO)CYCLOHEXYL]METHYL}-2-IMINO-3-METHYLIMIDAZOLIDIN-4-ONE'>3KT</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4r91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r91 OCA], [https://pdbe.org/4r91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r91 RCSB], [https://www.ebi.ac.uk/pdbsum/4r91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r91 ProSAT]</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=4r91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r91 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r91 RCSB], [http://www.ebi.ac.uk/pdbsum/4r91 PDBsum]</span></td></tr>
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</table>
</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4r91" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Memapsin 2]]
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[[Category: Homo sapiens]]
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[[Category: Caldwell, J P.]]
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[[Category: Large Structures]]
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[[Category: Orth, P.]]
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[[Category: Caldwell JP]]
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[[Category: Strickland, C.]]
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[[Category: Orth P]]
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[[Category: Aspartic protease]]
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[[Category: Strickland C]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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Current revision

BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(cyclopentylamino)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium

PDB ID 4r91

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