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| | ==Crystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a co-crystallization experiment== | | ==Crystal Structure of Human Beta Secretase in Complex with NVP-BXD552, derived from a co-crystallization experiment== |
| - | <StructureSection load='4d8c' size='340' side='right' caption='[[4d8c]], [[Resolution|resolution]] 2.07Å' scene=''> | + | <StructureSection load='4d8c' size='340' side='right'caption='[[4d8c]], [[Resolution|resolution]] 2.07Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4d8c]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D8C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4d8c]] 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=4D8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D8C FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BXD:(3S,4S,5R)-3-(4-AMINO-3-{[(2R)-3-ETHOXY-1,1,1-TRIFLUOROPROPAN-2-YL]OXY}-5-FLUOROBENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>BXD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.07Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3veu|3veu]], [[3vf3|3vf3]], [[3vg1|3vg1]], [[4d85|4d85]], [[4d88|4d88]], [[4d89|4d89]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BXD:(3S,4S,5R)-3-(4-AMINO-3-{[(2R)-3-ETHOXY-1,1,1-TRIFLUOROPROPAN-2-YL]OXY}-5-FLUOROBENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>BXD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4d8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8c OCA], [https://pdbe.org/4d8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d8c RCSB], [https://www.ebi.ac.uk/pdbsum/4d8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8c 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=4d8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d8c RCSB], [http://www.ebi.ac.uk/pdbsum/4d8c PDBsum]</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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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4d8c" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Beta secretase|Beta secretase]] | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Bourgier, E]] | + | [[Category: Bourgier E]] |
| - | [[Category: Rondeau, J M]] | + | [[Category: Rondeau JM]] |
| - | [[Category: Alzheimer's disease]]
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| - | [[Category: Aspartic proteinase]]
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| - | [[Category: Bace1]]
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| - | [[Category: Beta-secretase]]
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| - | [[Category: Enzyme inhibitor complex]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Memapsin2]]
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| - | [[Category: Structure-based drug design]]
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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
Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 mumol/kg demonstrated significant reduction of brain Abeta levels.
Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid beta-peptides.,Rueeger H, Lueoend R, Rogel O, Rondeau JM, Mobitz H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S, Neumann U J Med Chem. 2012 Apr 12;55(7):3364-86. Epub 2012 Mar 21. PMID:22380629[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
- ↑ Rueeger H, Lueoend R, Rogel O, Rondeau JM, Mobitz H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud S, Neumann U. Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid beta-peptides. J Med Chem. 2012 Apr 12;55(7):3364-86. Epub 2012 Mar 21. PMID:22380629 doi:10.1021/jm300069y
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