title: Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin.
abstract: Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ 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 Aβ. 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 Aβ, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ and breaks an essential salt-bridge characteristic of the β-hairpin conformation, eliminating features characteristic of the basic organization in Aβ 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 Aβ oligomers, and provide a strong rationale for the evaluation of crenezumab as a potential AD therapy.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Maurer
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Mathieu
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Oskar
authors.initials: O
authors.lastname: Adolfsson
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Bainbridge
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Germaine
authors.initials: G
authors.lastname: Fuh
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jasvinder K
authors.initials: JK
authors.lastname: Atwal
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang