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| | <StructureSection load='3h0b' size='340' side='right'caption='[[3h0b]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='3h0b' size='340' side='right'caption='[[3h0b]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3h0b]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H0B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3h0b]] 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=3H0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H0B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B35:4-[(1S)-1-(3-FLUORO-4-METHOXYPHENYL)-2-(2-METHOXY-5-NITROPHENYL)ETHYL]-1H-IMIDAZOL-2-AMINE'>B35</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]] 2.7Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, beta-secretase, KIAA1149 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B35:4-[(1S)-1-(3-FLUORO-4-METHOXYPHENYL)-2-(2-METHOXY-5-NITROPHENYL)ETHYL]-1H-IMIDAZOL-2-AMINE'>B35</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3h0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0b OCA], [https://pdbe.org/3h0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h0b RCSB], [https://www.ebi.ac.uk/pdbsum/3h0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0b ProSAT]</span></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=3h0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h0b OCA], [https://pdbe.org/3h0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h0b RCSB], [https://www.ebi.ac.uk/pdbsum/3h0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h0b ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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>
| + | [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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Allison TJ]] |
| - | [[Category: Allison, T J]] | + | |
| - | [[Category: Alternative splicing]]
| + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Zymogen]]
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1.,Stachel SJ, Coburn CA, Rush D, Jones KL, Zhu H, Rajapakse H, Graham SL, Simon A, Katharine Holloway M, Allison TJ, Munshi SK, Espeseth AS, Zuck P, Colussi D, Wolfe A, Pietrak BL, Lai MT, Vacca JP Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. Epub 2009 Apr 18. PMID:19409780[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
- ↑ Stachel SJ, Coburn CA, Rush D, Jones KL, Zhu H, Rajapakse H, Graham SL, Simon A, Katharine Holloway M, Allison TJ, Munshi SK, Espeseth AS, Zuck P, Colussi D, Wolfe A, Pietrak BL, Lai MT, Vacca JP. Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. Epub 2009 Apr 18. PMID:19409780 doi:10.1016/j.bmcl.2009.04.033
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