Ultsch, MarkLi, BingMaurer, TillMathieu, MaryAdolfsson, OskarMuhs, AndreasPfeifer, AndreaPihlgren, MariaBainbridge, Travis W.Reichelt, MikeErnst, James A.Eigenbrot, CharlesFuh, GermaineAtwal, Jasvinder K.Watts, Ryan J.Wang, Weiru2017-01-242017-01-242017-01-242016-12-0110.1038/srep39374https://infoscience.epfl.ch/handle/20.500.14299/133511WOS:000389978700001Accumulation of amyloid-beta (A beta) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of A beta remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-A beta monoclonal IgG4 that binds multiple forms of A beta, with higher affinity for aggregated forms, and that blocks A beta aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with A beta. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab's versatile binding profile. We find interactions consistent with high affinity for multiple forms of A beta, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of A beta and breaks an essential salt-bridge characteristic of the beta-hairpin conformation, eliminating features characteristic of the basic organization in A beta oligomers and fibrils, and explains crenezumab's inhibition of aggregation and promotion of disaggregation. These insights highlight crenezumab's unique mechanism of action, particularly regarding A beta oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy.text::journal::journal article::research article