6UJ0

Unbound BACE2 mutant structure

Summary for 6UJ0

• Entry DOI: 10.2210/pdb6uj0/pdb
• Descriptor: Beta-secretase 2, unidentified polypeptide (3 entities in total)
• Functional Keywords: aspartic protease, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 100111.49

Authors

Yen, Y.C.,Ghosh, A.K.,Mesecar, A.D. (deposition date: 2019-10-01, release date: 2020-10-07, Last modification date: 2024-10-23)

Primary citation

Yen, Y.C.,Kammeyer, A.M.,Tirlangi, J.,Ghosh, A.K.,Mesecar, A.D.
A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.
Acs Chem Neurosci, 12:581-588, 2021

PubMed Abstract: The ability to perform routine structure-guided drug design for selective BACE inhibitors has been limited because of the lack of robust platform for BACE2 expression, purification, and crystallization. To overcome this limitation, we developed a platform that produces 2-3 mg of pure BACE2 protein per liter of culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound was found to potently inhibit BACE 1 ( = 5 nM) with a selectivity of 214-fold over BACE2. The X-ray crystal structures of unbound BACE2 (2.2 Å) and BACE2 bound to compound (3.0 Å and = 7 nM) were determined and compared to the X-ray structures of BACE1 revealing the S1-S3 subsite as a selectivity determinant. This platform should enable a more rapid development of new and selective BACE inhibitors for the treatment of Alzheimer's disease or type II diabetes.

PubMed: 33544569
DOI: 10.1021/acschemneuro.0c00629

Experimental method

X-RAY DIFFRACTION (2.15 Å)