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| | ==Structure of BACE bound to SCH743813== | | ==Structure of BACE bound to SCH743813== |
| - | <StructureSection load='3lnk' size='340' side='right' caption='[[3lnk]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='3lnk' size='340' side='right'caption='[[3lnk]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3lnk]] is a 2 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=3LNK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LNK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3lnk]] is a 2 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=3LNK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LNK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=74A:N-{(1S,2S)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R)-4-(PHENYLCARBONYL)PIPERAZIN-2-YL]ETHYL}-5-METHYL-N,N-DIPROPYLBENZENE-1,3-DICARBOXAMIDE'>74A</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 1.8Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=74A:N-{(1S,2S)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R)-4-(PHENYLCARBONYL)PIPERAZIN-2-YL]ETHYL}-5-METHYL-N,N-DIPROPYLBENZENE-1,3-DICARBOXAMIDE'>74A</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=3lnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lnk OCA], [https://pdbe.org/3lnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lnk RCSB], [https://www.ebi.ac.uk/pdbsum/3lnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lnk ProSAT]</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=3lnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lnk OCA], [http://pdbe.org/3lnk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3lnk RCSB], [http://www.ebi.ac.uk/pdbsum/3lnk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3lnk 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: Cumming, J]] | + | [[Category: Cumming J]] |
| - | [[Category: Orth, P]] | + | [[Category: Orth P]] |
| - | [[Category: Alternative splicing]]
| + | |
| - | [[Category: Alzheimerss']]
| + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Bace1]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Endosome]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Golgi apparatus]]
| + | |
| - | [[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
With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2' sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Abeta(40) in transgenic mice with a single subcutaneous dose.
Piperazine sulfonamide BACE1 inhibitors: design, synthesis, and in vivo characterization.,Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau L, Greenlee W, Guo T, Kennedy M, Kuvelkar R, Le T, Li G, McHugh N, Orth P, Ozgur L, Parker E, Saionz K, Stamford A, Strickland C, Tadesse D, Voigt J, Zhang L, Zhang Q Bioorg Med Chem Lett. 2010 May 1;20(9):2837-42. Epub 2010 Mar 12. PMID:20347593[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
- ↑ Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau L, Greenlee W, Guo T, Kennedy M, Kuvelkar R, Le T, Li G, McHugh N, Orth P, Ozgur L, Parker E, Saionz K, Stamford A, Strickland C, Tadesse D, Voigt J, Zhang L, Zhang Q. Piperazine sulfonamide BACE1 inhibitors: design, synthesis, and in vivo characterization. Bioorg Med Chem Lett. 2010 May 1;20(9):2837-42. Epub 2010 Mar 12. PMID:20347593 doi:10.1016/j.bmcl.2010.03.050
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