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| | <StructureSection load='4pzx' size='340' side='right'caption='[[4pzx]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='4pzx' size='340' side='right'caption='[[4pzx]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pzx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PZX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PZX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pzx]] is a 1 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=4PZX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PZX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2X5:(4R,4AR,10AR)-7-(5-CHLOROPYRIDIN-3-YL)-3,4,4A,10A-TETRAHYDRO-1H-SPIRO[1,3-OXAZOLE-4,5-PYRANO[3,4-B]CHROMEN]-2-AMINE'>2X5</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2X5:(4R,4AR,10AR)-7-(5-CHLOROPYRIDIN-3-YL)-3,4,4A,10A-TETRAHYDRO-1H-SPIRO[1,3-OXAZOLE-4,5-PYRANO[3,4-B]CHROMEN]-2-AMINE'>2X5</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pzw|4pzw]]</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=4pzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pzx OCA], [https://pdbe.org/4pzx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pzx RCSB], [https://www.ebi.ac.uk/pdbsum/4pzx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pzx ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://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'>[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>
| + | |
| - | <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=4pzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pzx OCA], [http://pdbe.org/4pzx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pzx RCSB], [http://www.ebi.ac.uk/pdbsum/4pzx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pzx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> | + | [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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Vigers GPA]] |
| - | [[Category: Vigers, G P.A]] | + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| 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 PubMed
The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110nM) demonstrated a reduction in CSF Abeta in wild type rats after a single dose.
Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors.,Volgraf M, Chan L, Huestis MP, Purkey HE, Burkard M, Geck Do M, Harris J, Hunt KW, Liu X, Lyssikatos JP, Rana S, Thomas AA, Vigers GP, Siu M Bioorg Med Chem Lett. 2014 Jun 1;24(11):2477-80. doi: 10.1016/j.bmcl.2014.04.012., Epub 2014 Apr 13. PMID:24780121[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Volgraf M, Chan L, Huestis MP, Purkey HE, Burkard M, Geck Do M, Harris J, Hunt KW, Liu X, Lyssikatos JP, Rana S, Thomas AA, Vigers GP, Siu M. Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. Bioorg Med Chem Lett. 2014 Jun 1;24(11):2477-80. doi: 10.1016/j.bmcl.2014.04.012., Epub 2014 Apr 13. PMID:24780121 doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.012
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