5lua
Crystal structure of human legumain (AEP) in complex with compound 11b
Structural highlights
FunctionLGMN_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 PubMeddelta-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
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