View source for 6dhc


==X-ray structure of BACE1 in complex with a bicyclic isoxazoline carboxamide as the P3 ligand==
<StructureSection load='6dhc' size='340' side='right'caption='[[6dhc]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dhc]] is a 3 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=6DHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DHC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GHJ:(3~{R},3~{a}~{R},6~{a}~{S})-~{N}-[(2~{R})-1-[[(4~{S},5~{S},7~{R})-2,7-dimethyl-8-[[(2~{S})-3-methyl-1-(2-methylpropylamino)-1-oxidanylidene-butan-2-yl]amino]-5-oxidanyl-8-oxidanylidene-octan-4-yl]amino]-3-methylsulfanyl-1-oxidanylidene-propan-2-yl]-2,3,3~{a},4,5,6~{a}-hexahydrofuro[3,2-d][1,2]oxazole-3-carboxamide'>GHJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=URE:UREA'>URE</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=6dhc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dhc OCA], [https://pdbe.org/6dhc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dhc RCSB], [https://www.ebi.ac.uk/pdbsum/6dhc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dhc ProSAT]</span></td></tr>
</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 ==
We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9nM and EC50 of 343nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85A resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.

Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand.,Ghosh AK, Ghosh K, Brindisi M, Lendy EK, Yen YC, Kumaragurubaran N, Huang X, Tang J, Mesecar AD Bioorg Med Chem Lett. 2018 Jun 26. pii: S0960-894X(18)30546-8. doi:, 10.1016/j.bmcl.2018.06.045. PMID:29970308<ref>PMID:29970308</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dhc" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lendy EK]]
[[Category: Mesecar AD]]