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.com
Volume 3, Issue 2
ISSN: 2470-9905
Crystallography 2017
October 16-17, 2017
2
nd
International Conference on
October 16-17, 2017 | Chicago, USA
Applied Crystallography
Weiru Wang, Struct Chem Crystallogr Commun, 3:2
DOI: 10.21767/2470-9905-C1-002
Structural insights into Crenezumab’s mechanism of action
Weiru Wang
Genentech, USA
C
renezumab is a fully humanized immunoglobulin isotype G4 (IgG4) monoclonal antibody that binds to monomeric as well
as aggregated Aβ forms (oligomers, fibers and plaques). Notably, crenezumab binds with higher affinity to Aβ oligomers over
monomers and
in vitro
studies have demonstrated crenezumab’s ability to block Aβ aggregation and promote Aβ disaggregation.
To understand the structural basis for this activity and crenezumab’s broad binding profile, we determined the crystal structure
of crenezumab in complex with Aβ. The structure reveals a sequential epitope and the 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 formultiple forms of Aβ, particularly oligomers. 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 treatment for patients with Alzheimer’s disease.
Biography
Weiru Wang has completed his PhD in Biophysics from Cornell University and Post-doctoral studies from University of California, Berkeley. He is currently a Senior Scien-
tist and a Group Leader in the Structural Biology Department at Genentech, a member of the Roche Group. His research focuses on understanding of molecular basis of
protein-drug interactions using biophysical methods, primarily macromolecular crystallography.
wang.weiru@gene.com