6GFE

High-resolution Structure of a therapeutic full-length anti-NPRA Antibody with exceptional Conformational Diversity

Summary for 6GFE

• Entry DOI: 10.2210/pdb6gfe/pdb
• Descriptor: Immunoglobulin gamma-4 heavy chain, Immunoglobulin gamma-4 light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: immunoglobulin, antibody, natriuretic peptide receptor a, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 149267.04

Authors

Hoerer, S. (deposition date: 2018-04-30, release date: 2019-05-15, Last modification date: 2024-10-16)

Primary citation

Blech, M.,Horer, S.,Kuhn, A.B.,Kube, S.,Goddeke, H.,Kiefer, H.,Zang, Y.,Alber, Y.,Kast, S.M.,Westermann, M.,Tully, M.D.,Schafer, L.V.,Garidel, P.
Structure of a Therapeutic Full-Length Anti-NPRA IgG4 Antibody: Dissecting Conformational Diversity.
Biophys.J., 116:1637-1649, 2019

PubMed Abstract: We report the x-ray crystal structure of intact, full-length human immunoglobulin (IgG4) at 1.8 Å resolution. The data for IgG4 (S228P), an antibody targeting the natriuretic peptide receptor A, show a previously unrecognized type of Fab-Fc orientation with a distorted λ-shape in which one Fab-arm is oriented toward the Fc portion. Detailed structural analysis by x-ray crystallography and molecular simulations suggest that this is one of several conformations coexisting in a dynamic equilibrium state. These results were confirmed by small angle x-ray scattering in solution. Furthermore, electron microscopy supported these findings by preserving molecule classes of different conformations. This study fosters our understanding of IgG4 in particular and our appreciation of antibody flexibility in general. Moreover, we give insights into potential biological implications, specifically for the interaction of human anti-natriuretic peptide receptor A IgG4 with the neonatal Fc receptor, Fcγ receptors, and complement-activating C1q by considering conformational flexibility.

PubMed: 31023536
DOI: 10.1016/j.bpj.2019.03.036

Experimental method

X-RAY DIFFRACTION (1.8 Å)