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| | ==Bace1 in complex with the aminopyridine Compound 44== | | ==Bace1 in complex with the aminopyridine Compound 44== |
| - | <StructureSection load='3l38' size='340' side='right' caption='[[3l38]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='3l38' size='340' side='right'caption='[[3l38]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3l38]] 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=3L38 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3L38 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3l38]] 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=3L38 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3L38 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=879:6-({2-(2-CHLOROPHENYL)-5-[4-(PYRIMIDIN-5-YLOXY)PHENYL]-1H-PYRROL-1-YL}METHYL)PYRIDIN-2-AMINE'>879</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]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3l3a|3l3a]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=879:6-({2-(2-CHLOROPHENYL)-5-[4-(PYRIMIDIN-5-YLOXY)PHENYL]-1H-PYRROL-1-YL}METHYL)PYRIDIN-2-AMINE'>879</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3l38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l38 OCA], [https://pdbe.org/3l38 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3l38 RCSB], [https://www.ebi.ac.uk/pdbsum/3l38 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3l38 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>
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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=3l38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l38 OCA], [http://pdbe.org/3l38 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3l38 RCSB], [http://www.ebi.ac.uk/pdbsum/3l38 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3l38 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l3/3l38_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l3/3l38_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | ==See Also== | | ==See Also== |
| - | *[[Beta secretase|Beta secretase]] | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Chopra, R]] | + | [[Category: Chopra R]] |
| - | [[Category: Olland, A M]] | + | [[Category: Olland AM]] |
| - | [[Category: Aminopyridine]]
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| - | [[Category: Aspartyl protease]]
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| - | [[Category: Bace-1]]
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| - | [[Category: Beta-secretase]]
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| - | [[Category: Disulfide bond]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Inhibitor]]
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| - | [[Category: Protease]]
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| - | [[Category: Transmembrane]]
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| - | [[Category: Zymogen]]
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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]
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
The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.
Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.,Malamas MS, Barnes K, Hui Y, Johnson M, Lovering F, Condon J, Fobare W, Solvibile W, Turner J, Hu Y, Manas ES, Fan K, Olland A, Chopra R, Bard J, Pangalos MN, Reinhart P, Robichaud AJ Bioorg Med Chem Lett. 2010 Apr 1;20(7):2068-73. Epub 2010 Feb 23. PMID:20223661[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
- ↑ Malamas MS, Barnes K, Hui Y, Johnson M, Lovering F, Condon J, Fobare W, Solvibile W, Turner J, Hu Y, Manas ES, Fan K, Olland A, Chopra R, Bard J, Pangalos MN, Reinhart P, Robichaud AJ. Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2068-73. Epub 2010 Feb 23. PMID:20223661 doi:10.1016/j.bmcl.2010.02.075
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