PDBsum entry 5mco

Hydrolase

PDB id: 5mco

Contents

Protein chain

383 a.a.

Ligands

ACE-ALA-LEU-TYR-PRO-TYR-PHE-LEU-PRO-ILE

BSD

Waters ×197

PDB id:

5mco

Name:

Hydrolase

Title:

Crystal structure of bace-1 in complex with active site inhibitor grl- 8234 and exosite peptide

Structure:

Beta-secretase 1. Chain: a. Synonym: aspartyl protease 2,asp 2,beta-site amyloid precursor protein cleaving enzyme 1,beta-site app cleaving enzyme 1,memapsin-2, membrane-associated aspartic protease 2. Engineered: yes. Mutation: yes. Bace-1 exosite peptide. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

2.49Å R-factor: 0.177 R-free: 0.223

Authors:

A.Kuglstatter,M.Stihle,J.Benz

Key ref:

N.Ruderisch et al. (2017). Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport. EBioMedicine, 24, 76-92. PubMed id: 28923680

Date:

10-Nov-16 Release date: 27-Sep-17

Protein chain

P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens

Seq: 501 a.a.

Struc: 383 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.23.46 - memapsin 2.

EBioMedicine 24:76-92 (2017)

PubMed id: 28923680

Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport.

N.Ruderisch, D.Schlatter, A.Kuglstatter, W.Guba, S.Huber, C.Cusulin, J.Benz, A.C.Rufer, J.Hoernschemeyer, C.Schweitzer, T.Bülau, A.Gärtner, E.Hoffmann, J.Niewoehner, C.Patsch, K.Baumann, H.Loetscher, E.Kitas, P.O.Freskgård.

ABSTRACT

Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) 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 Aβ 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 Aβ. 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.