6uj1 | pdb_00006uj1
BACE2 mutant in complex with a macrocyclic compound
Structural highlights
FunctionBACE2_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 E. coli culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound 2 was found to potently inhibit BACE 1 (Ki = 5 nM) with a selectivity of 214-fold over BACE2. The X-ray crystal structures of unbound BACE2 (2.2 A) and BACE2 bound to compound 3 (3.0 A and Ki = 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. A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.,Yen YC, Kammeyer AM, Tirlangi J, Ghosh AK, Mesecar AD ACS Chem Neurosci. 2021 Feb 17;12(4):581-588. doi: 10.1021/acschemneuro.0c00629. , Epub 2021 Feb 5. PMID:33544569[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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