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5LU8

CRYSTAL STRUCTURE OF YVAD-CMK BOUND HUMAN LEGUMAIN (AEP) IN COMPLEX WITH COMPOUND 11B

Summary for 5LU8
Entry DOI10.2210/pdb5lu8/pdb
Related PRD IDPRD_002086
DescriptorAC-TYR-VAL-ALA-ASP-CHLOROMETHYLKETONE, Legumain, SULFATE ION, ... (7 entities in total)
Functional Keywordscysteine protease, allosteric inhibitor, asparaginyl endopeptidase, alzheimer's disease, hydrolase
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight31754.30
Authors
Dall, E.,Ye, K.,Brandstetter, H. (deposition date: 2016-09-08, release date: 2017-03-29, Last modification date: 2024-11-13)
Primary citationZhang, Z.,Obianyo, O.,Dall, E.,Du, Y.,Fu, H.,Liu, X.,Kang, S.S.,Song, M.,Yu, S.P.,Cabrele, C.,Schubert, M.,Li, X.,Wang, J.Z.,Brandstetter, H.,Ye, K.
Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
Nat Commun, 8:14740-14740, 2017
Cited by
PubMed Abstract: δ-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-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-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 δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.
PubMed: 28345579
DOI: 10.1038/ncomms14740
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.95 Å)
Structure validation

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