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| | ==Fragment Based Discovery and Optimisation of BACE-1 Inhibitors== | | ==Fragment Based Discovery and Optimisation of BACE-1 Inhibitors== |
| - | <StructureSection load='3msl' size='340' side='right' caption='[[3msl]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='3msl' size='340' side='right'caption='[[3msl]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3msl]] 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=3MSL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MSL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3msl]] 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=3MSL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MSL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EV5:(3S)-3-(2-AMINO-5-CHLORO-1H-BENZIMIDAZOL-1-YL)-N-(CYCLOHEXYLMETHYL)PENTANAMIDE'>EV5</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3msj|3msj]], [[3msk|3msk]], [[3msm|3msm]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EV5:(3S)-3-(2-AMINO-5-CHLORO-1H-BENZIMIDAZOL-1-YL)-N-(CYCLOHEXYLMETHYL)PENTANAMIDE'>EV5</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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 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=3msl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3msl OCA], [https://pdbe.org/3msl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3msl RCSB], [https://www.ebi.ac.uk/pdbsum/3msl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3msl 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=3msl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3msl OCA], [http://pdbe.org/3msl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3msl RCSB], [http://www.ebi.ac.uk/pdbsum/3msl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3msl 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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| | ==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: Barker, J]] | + | [[Category: Barker J]] |
| - | [[Category: Madden, J]] | + | [[Category: Madden J]] |
| - | [[Category: Smith, M]] | + | [[Category: Smith M]] |
| - | [[Category: Alzheimer's disease]]
| + | |
| - | [[Category: Amyloid precursor protein secretase]]
| + | |
| - | [[Category: Aspartic endopeptidase]]
| + | |
| - | [[Category: Aspartic protease]]
| + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Base]]
| + | |
| - | [[Category: Beta-secretase]]
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| - | [[Category: Fluorescence polarisation]]
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| - | [[Category: Fragment-based drug design]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Protease]]
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| - | [[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
A novel series of 2-aminobenzimidazole inhibitors of BACE1 has been discovered using fragment-based drug discovery (FBDD) techniques. The rapid optimization of these inhibitors using structure-guided medicinal chemistry is discussed.
Fragment-based discovery and optimization of BACE1 inhibitors.,Madden J, Dod JR, Godemann R, Kraemer J, Smith M, Biniszkiewicz M, Hallett DJ, Barker J, Dyekjaer JD, Hesterkamp T Bioorg Med Chem Lett. 2010 Sep 1;20(17):5329-33. Epub 2010 Jun 27. PMID:20656487[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
- ↑ Madden J, Dod JR, Godemann R, Kraemer J, Smith M, Biniszkiewicz M, Hallett DJ, Barker J, Dyekjaer JD, Hesterkamp T. Fragment-based discovery and optimization of BACE1 inhibitors. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5329-33. Epub 2010 Jun 27. PMID:20656487 doi:10.1016/j.bmcl.2010.06.089
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