PDBsum entry 5lua

Hydrolase

PDB id: 5lua

Contents

Protein chains

262 a.a.

Ligands

NAG-NAG ×3

NAG ×2

5KN

Waters ×272

PDB id:

5lua

Name:

Hydrolase

Title:

Crystal structure of human legumain (aep) in complex with compound 11b

Structure:

Legumain. Chain: a, b. Fragment: unp residues 26-287. Synonym: asparaginyl endopeptidase,protease,cysteine 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lgmn, prsc1. Expressed in: leishmania tarentolae. Expression_system_taxid: 5689

Resolution:

2.00Å R-factor: 0.223 R-free: 0.252

Authors:

E.Dall,K.Ye,H.Brandstetter

Key ref:

Z.Zhang et al. (2017). Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. Nat Commun, 8, 14740. PubMed id: 28345579 DOI: 10.1038/ncomms14740

Date:

08-Sep-16 Release date: 29-Mar-17

Protein chains

Q99538  (LGMN_HUMAN) -  Legumain from Homo sapiens

Seq: 433 a.a.

Struc: 262 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.22.34 - legumain.
• Reaction: Hydrolysis of proteins and small-molecule substrates at -Asn-|-Xaa- bonds.

DOI no: 10.1038/ncomms14740

Nat Commun 8:14740 (2017)

PubMed id: 28345579

Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.

Z.Zhang, O.Obianyo, E.Dall, Y.Du, H.Fu, X.Liu, S.S.Kang, M.Song, S.P.Yu, C.Cabrele, M.Schubert, X.Li, J.Z.Wang, H.Brandstetter, K.Ye.

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.