3EYU

PFA1 Fab fragment complexed with Ror2(518-525)

Summary for 3EYU

• Entry DOI: 10.2210/pdb3eyu/pdb
• Related: 3EYS
• Descriptor: If kappa light chain, PFA1 Fab Heavy Chain, ROR2(518-525) peptide, ... (4 entities in total)
• Functional Keywords: fab, amyloid, alzheimer's, protein-peptide complex, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 3
• Total formula weight: 49490.21

Authors

Gardberg, A.S.,Dealwis, C.G. (deposition date: 2008-10-21, release date: 2009-05-12, Last modification date: 2023-12-27)

Primary citation

Gardberg, A.,Dice, L.,Pridgen, K.,Ko, J.,Patterson, P.,Ou, S.,Wetzel, R.,Dealwis, C.
Structures of Abeta-related peptide--monoclonal antibody complexes.
Biochemistry, 48:5210-5217, 2009

PubMed Abstract: 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 Abeta N-terminus. The monoclonal anti-Abeta Ab PFA1 recognizes the EFRH epitope of Abeta. PFA1 has a high affinity for Abeta fibrils and protofibrils (0.1 nM), as well as good affinity for Abeta monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyroglutamate peptide pyro-Glu3-Abeta with a 77-fold loss in affinity compared to the WT Abeta(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 Abeta(1-8). In this work, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-Abeta peptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 A, respectively. As with wild-type Abeta, 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 Abeta(1-8), Grip1, pyro-Glu3-Abeta(3-8), and Ror2 in complex with PFA1 shows that the greatest conformational flexibility occurs at residues 2 to 3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1 and its ability to recognize Abeta N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyroglutamate Abeta.

PubMed: 19385664
DOI: 10.1021/bi9001216

Experimental method

X-RAY DIFFRACTION (2.71 Å)