4XXD

Crystal Structure of mid-region amyloid beta capture by solanezumab

Summary for 4XXD

• Entry DOI: 10.2210/pdb4xxd/pdb
• Descriptor: Fab Light Chain, Fab Heavy Chain, Amyloid-beta fragment, ... (4 entities in total)
• Functional Keywords: fab, amyloid-beta, immune system
• Biological source: Homo sapiens; More
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 6
• Total formula weight: 99473.10

Authors

Hermans, S.J.,Crespi, G.A.N.,Parker, M.W.,Miles, L.A. (deposition date: 2015-01-30, release date: 2015-04-29, Last modification date: 2024-10-23)

Primary citation

Crespi, G.A.,Hermans, S.J.,Parker, M.W.,Miles, L.A.
Molecular basis for mid-region amyloid-beta capture by leading Alzheimer's disease immunotherapies.
Sci Rep, 5:9649-9649, 2015

PubMed Abstract: Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å(2) buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core. The conformation of Aβ captured is an intermediate between observed sheet and helical forms with intramolecular hydrogen bonds stabilising residues 20-26 in a helical conformation. Remarkably, Aβ-binding residues are almost perfectly conserved in crenezumab. The structure explains the observed shared cross reactivity of solanezumab and crenezumab with proteins abundant in plasma that exhibit this Phe-Phe dipeptide.

PubMed: 25880481
DOI: 10.1038/srep09649

Experimental method

X-RAY DIFFRACTION (2.41 Å)