5WHK

Crystal structure of Fab fragment of antibody DX-2507 bound to FcRn-B2M

Summary for 5WHK

• Entry DOI: 10.2210/pdb5whk/pdb
• Descriptor: DX-2507 Fab heavy chain, DX-2507 Fab light chain, IgG receptor FcRn large subunit p51, ... (7 entities in total)
• Functional Keywords: neonatal receptor, fc, antibody recycling, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P55899; Secreted . Note=(Microbial infection) In the presence of M: P61769
• Total number of polymer chains: 4
• Total formula weight: 92737.03

Authors

Edwards, T.E.,Clifton, M.C.,Nixon, A.E.,Kenniston, J.A. (deposition date: 2017-07-17, release date: 2017-09-06, Last modification date: 2024-10-16)

Primary citation

Kenniston, J.A.,Taylor, B.M.,Conley, G.P.,Cosic, J.,Kopacz, K.J.,Lindberg, A.P.,Comeau, S.R.,Atkins, K.,Bullen, J.,TenHoor, C.,Adelman, B.A.,Sexton, D.J.,Edwards, T.E.,Nixon, A.E.
Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody.
J. Biol. Chem., 292:17449-17460, 2017

PubMed Abstract: The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial from an immunological perspective in maintaining IgG populations, FcRn can contribute to the pathogenesis of autoimmune disorders when an abnormal immune response targets normal biological components. We previously described a monoclonal antibody (DX-2507) that binds to FcRn with high affinity at both neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we report a 2.5 Å resolution X-ray crystal structure of an FcRn-DX-2507 Fab complex, revealing a nearly complete overlap of the IgG-Fc binding site in FcRn by complementarity-determining regions in DX-2507. This overlap explains how DX-2507 blocks IgG binding to FcRn and thereby shortens IgG half-life by preventing IgGs from recycling back into circulation. Moreover, the complex structure explains how the DX-2507 interaction is pH-insensitive unlike normal Fc interactions and how serum albumin levels are unaffected by DX-2507 binding. These structural studies could inform antibody-based therapeutic approaches for limiting the effects of IgG-mediated autoimmune disease.

PubMed: 28878017
DOI: 10.1074/jbc.M117.807396

Experimental method

X-RAY DIFFRACTION (2.5 Å)