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| | ==BACE1 compound 23== | | ==BACE1 compound 23== |
| - | <StructureSection load='6ej3' size='340' side='right' caption='[[6ej3]], [[Resolution|resolution]] 1.94Å' scene=''> | + | <StructureSection load='6ej3' size='340' side='right'caption='[[6ej3]], [[Resolution|resolution]] 1.94Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ej3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EJ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EJ3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ej3]] 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=6EJ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EJ3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B7T:(1r,4r)-4-methoxy-6-(5-methyl-3-pyridinyl)-3H-dispiro[cyclohexane-1,2-indene-1,4-[1,3]oxazol]-2-amine'>B7T</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.94Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ej2|6ej2]]</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=6ej3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ej3 OCA], [https://pdbe.org/6ej3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ej3 RCSB], [https://www.ebi.ac.uk/pdbsum/6ej3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ej3 ProSAT]</span></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=6ej3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ej3 OCA], [http://pdbe.org/6ej3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ej3 RCSB], [http://www.ebi.ac.uk/pdbsum/6ej3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ej3 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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| | </div> | | </div> |
| | <div class="pdbe-citations 6ej3" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6ej3" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Memapsin 2]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Johansson, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Alzheimer]] | + | [[Category: Johansson P]] |
| - | [[Category: Bace1]]
| + | |
| - | [[Category: Peptide binding protein]]
| + | |
| - | [[Category: Protease]]
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| 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
BACE1 is responsible for the first step in APP proteolysis, leading to toxic Abeta production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited approximately 50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.
Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity.,Johansson P, Kaspersson K, Gurrell IK, Back E, Eketjall S, Scott CW, Cebers G, Thorne P, McKenzie MJ, Beaton H, Davey P, Kolmodin K, Holenz J, Duggan ME, Budd Haeberlein S, Burli RW J Med Chem. 2018 Apr 10. doi: 10.1021/acs.jmedchem.7b01716. PMID:29617572[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
- ↑ Johansson P, Kaspersson K, Gurrell IK, Back E, Eketjall S, Scott CW, Cebers G, Thorne P, McKenzie MJ, Beaton H, Davey P, Kolmodin K, Holenz J, Duggan ME, Budd Haeberlein S, Burli RW. Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity. J Med Chem. 2018 Apr 10. doi: 10.1021/acs.jmedchem.7b01716. PMID:29617572 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01716
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