6UJ0

Unbound BACE2 mutant structure

6UJ0 の概要

• エントリーDOI: 10.2210/pdb6uj0/pdb
• 分子名称: Beta-secretase 2, unidentified polypeptide (3 entities in total)
• 機能のキーワード: aspartic protease, peptide binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 100111.49

構造登録者

Yen, Y.C.,Ghosh, A.K.,Mesecar, A.D. (登録日: 2019-10-01, 公開日: 2020-10-07, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.15 Å)