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| | ==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-[3-[(3-chloro-8-quinolyl)amino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine== | | ==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-[3-[(3-chloro-8-quinolyl)amino]phenyl]-5-methyl-2,6-dihydro-1,4-oxazin-3-amine== |
| - | <StructureSection load='5f00' size='340' side='right' caption='[[5f00]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='5f00' size='340' side='right'caption='[[5f00]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5f00]] 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=5F00 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F00 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5f00]] 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=5F00 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F00 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5T8:(5~{R})-5-[3-[(3-CHLORANYLQUINOLIN-8-YL)AMINO]PHENYL]-5-METHYL-2,6-DIHYDRO-1,4-OXAZIN-3-AMINE'>5T8</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ezx|5ezx]], [[5ezz|5ezz]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5T8:(5~{R})-5-[3-[(3-CHLORANYLQUINOLIN-8-YL)AMINO]PHENYL]-5-METHYL-2,6-DIHYDRO-1,4-OXAZIN-3-AMINE'>5T8</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=5f00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f00 OCA], [https://pdbe.org/5f00 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f00 RCSB], [https://www.ebi.ac.uk/pdbsum/5f00 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f00 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=5f00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f00 OCA], [http://pdbe.org/5f00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f00 RCSB], [http://www.ebi.ac.uk/pdbsum/5f00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f00 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 5f00" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5f00" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[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: Banner, D]] | + | [[Category: Banner D]] |
| - | [[Category: Benz, J]] | + | [[Category: Benz J]] |
| - | [[Category: Kuglstatter, A]] | + | [[Category: Kuglstatter A]] |
| - | [[Category: Stihle, M]] | + | [[Category: Stihle M]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Protease inhibitor]]
| + | |
| 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
We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.
A Real-World Perspective on Molecular Design.,Kuhn B, Guba W, Hert J, Banner D, Bissantz C, Ceccarelli S, Haap W, Korner M, Kuglstatter A, Lerner C, Mattei P, Neidhart W, Pinard E, Rudolph MG, Schulz-Gasch T, Woltering T, Stahl M J Med Chem. 2016 Feb 24. PMID:26878596[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
- ↑ Kuhn B, Guba W, Hert J, Banner D, Bissantz C, Ceccarelli S, Haap W, Korner M, Kuglstatter A, Lerner C, Mattei P, Neidhart W, Pinard E, Rudolph MG, Schulz-Gasch T, Woltering T, Stahl M. A Real-World Perspective on Molecular Design. J Med Chem. 2016 Feb 24. PMID:26878596 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01875
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