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| | ==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE INHIBITOR GRL-8234 AND EXOSITE PEPTIDE== | | ==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE INHIBITOR GRL-8234 AND EXOSITE PEPTIDE== |
| - | <StructureSection load='5mco' size='340' side='right' caption='[[5mco]], [[Resolution|resolution]] 2.49Å' scene=''> | + | <StructureSection load='5mco' size='340' side='right'caption='[[5mco]], [[Resolution|resolution]] 2.49Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mco]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MCO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MCO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mco]] 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=5MCO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MCO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BSD:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]BENZENE-1,3-DICARBOXAMIDE'>BSD</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]] 2.49Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=BSD:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]BENZENE-1,3-DICARBOXAMIDE'>BSD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5mbw|5mbw]]</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=5mco FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mco OCA], [https://pdbe.org/5mco PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mco RCSB], [https://www.ebi.ac.uk/pdbsum/5mco PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mco 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=5mco FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mco OCA], [http://pdbe.org/5mco PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mco RCSB], [http://www.ebi.ac.uk/pdbsum/5mco PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mco 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 5mco" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5mco" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Memapsin 2]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Benz, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Kuglstatter, A]] | + | [[Category: Benz J]] |
| - | [[Category: Stihle, M]] | + | [[Category: Kuglstatter A]] |
| - | [[Category: Hydrolase]] | + | [[Category: Stihle M]] |
| - | [[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
Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidbeta (Abeta) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Abeta levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Abeta. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.
Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Abeta Levels Mediated by Brain Shuttle Transport.,Ruderisch N, Schlatter D, Kuglstatter A, Guba W, Huber S, Cusulin C, Benz J, Rufer AC, Hoernschemeyer J, Schweitzer C, Bulau T, Gartner A, Hoffmann E, Niewoehner J, Patsch C, Baumann K, Loetscher H, Kitas E, Freskgard PO EBioMedicine. 2017 Sep 7. pii: S2352-3964(17)30351-1. doi:, 10.1016/j.ebiom.2017.09.004. PMID:28923680[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
- ↑ Ruderisch N, Schlatter D, Kuglstatter A, Guba W, Huber S, Cusulin C, Benz J, Rufer AC, Hoernschemeyer J, Schweitzer C, Bulau T, Gartner A, Hoffmann E, Niewoehner J, Patsch C, Baumann K, Loetscher H, Kitas E, Freskgard PO. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Abeta Levels Mediated by Brain Shuttle Transport. EBioMedicine. 2017 Sep 7. pii: S2352-3964(17)30351-1. doi:, 10.1016/j.ebiom.2017.09.004. PMID:28923680 doi:http://dx.doi.org/10.1016/j.ebiom.2017.09.004
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