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| | ==CRYSTAL STRUCTURE OF YVAD-CMK BOUND HUMAN LEGUMAIN (AEP) IN COMPLEX WITH COMPOUND 11B== | | ==CRYSTAL STRUCTURE OF YVAD-CMK BOUND HUMAN LEGUMAIN (AEP) IN COMPLEX WITH COMPOUND 11B== |
| - | <StructureSection load='5lu8' size='340' side='right' caption='[[5lu8]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='5lu8' size='340' side='right'caption='[[5lu8]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lu8]] 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=5LU8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LU8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lu8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LU8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LU8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5KN:2,4-DI(MORPHOLIN-4-YL)ANILINE'>5KN</scene>, <scene name='pdbligand=EMC:ETHYL+MERCURY+ION'>EMC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 1.95Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=SNN:L-3-AMINOSUCCINIMIDE'>SNN</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=5KN:2,4-DI(MORPHOLIN-4-YL)ANILINE'>5KN</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=EMC:ETHYL+MERCURY+ION'>EMC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PRD_002086:ACE-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE'>PRD_002086</scene>, <scene name='pdbligand=SNN:L-3-AMINOSUCCINIMIDE'>SNN</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">LGMN, PRSC1 ([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=5lu8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lu8 OCA], [https://pdbe.org/5lu8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lu8 RCSB], [https://www.ebi.ac.uk/pdbsum/5lu8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lu8 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/Legumain Legumain], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.34 3.4.22.34] </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=5lu8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lu8 OCA], [http://pdbe.org/5lu8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lu8 RCSB], [http://www.ebi.ac.uk/pdbsum/5lu8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lu8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LGMN_HUMAN LGMN_HUMAN]] Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. | + | [https://www.uniprot.org/uniprot/LGMN_HUMAN LGMN_HUMAN] Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Legumain]] | + | [[Category: Large Structures]] |
| - | [[Category: Brandstetter, H]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Dall, E]] | + | [[Category: Brandstetter H]] |
| - | [[Category: Ye, K]] | + | [[Category: Dall E]] |
| - | [[Category: Allosteric inhibitor]] | + | [[Category: Ye K]] |
| - | [[Category: Alzheimer's disease]]
| + | |
| - | [[Category: Asparaginyl endopeptidase]]
| + | |
| - | [[Category: Cysteine protease]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
5lu8 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.95Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
LGMN_HUMAN Has a strict specificity for hydrolysis of asparaginyl bonds. Can also cleave aspartyl bonds slowly, especially under acidic conditions. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system.
Publication Abstract from PubMed
delta-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-beta and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable delta-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective delta-secretase inhibitor, termed compound 11, that specifically blocks delta-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this delta-secretase inhibitor may be an effective clinical therapeutic agent towards AD.
Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.,Zhang Z, Obianyo O, Dall E, Du Y, Fu H, Liu X, Kang SS, Song M, Yu SP, Cabrele C, Schubert M, Li X, Wang JZ, Brandstetter H, Ye K Nat Commun. 2017 Mar 27;8:14740. doi: 10.1038/ncomms14740. PMID:28345579[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Z, Obianyo O, Dall E, Du Y, Fu H, Liu X, Kang SS, Song M, Yu SP, Cabrele C, Schubert M, Li X, Wang JZ, Brandstetter H, Ye K. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. Nat Commun. 2017 Mar 27;8:14740. doi: 10.1038/ncomms14740. PMID:28345579 doi:http://dx.doi.org/10.1038/ncomms14740
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