Passive immunotherapy (PI) is being explored as a potential therapeutic against Alzheimer’s disease. The most promising antibodies (Abs) used in PI target the EFRH motif of the Aβ N-terminus. The monoclonal anti-Aβ Ab PFA1 recognizes the EFRH epitope of Aβ. PFA1 has a high affinity for Aβ fibrils and protofibrils (0.1 nM), as well as good affinity for Aβ monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyro-glutamate peptide pyro-Glu3-Aβ with a 77-fold loss in affinity compared to the WT Aβ(1–8). Furthermore, our earlier work illustrated PFA1’s potential for cross-reactivity. The receptor tyrosine kinase Ror2, which plays a role in skeletal and bone formation, possesses the EFRH sequence. PFA1 Fab binds the Ror2(518–525) peptide sequence REEFRHEA with a 3-fold enhancement over WT Aβ(1–8). In this work, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-Aβ peptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 Å, respectively. As with wild type Aβ, these peptides bind to the Fab via a combination of charge- and shape-complementarity, hydrogen bonding, and hydrophobic interactions. Comparison of the structures of the four peptides Aβ(1–8), Grip1, pyro-Glu3-Aβ and Ror2 in complex with PFA-1 show that the greatest conformational flexibility occurs at residues 2–3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1 and its ability to recognize Aβ N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyro-Glutamate Aβ.
A sexual health clinic implemented for university students in Birmingham, Alabama, found increased screening for certain populations and increased extragenital screening for men who have sex with men.
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