2J6E

Crystal Structure of an Autoimmune Complex between a Human IgM Rheumatoid Factor and IgG1 Fc reveals a Novel Fc Epitope and Evidence for Affinity Maturation

Summary for 2J6E

• Entry DOI: 10.2210/pdb2j6e/pdb
• Related: 1AJ7 1AQK 1D5B 1D5I 1D6V 1DN2 1E4K 1FC1 1FC2 1FCC 1H3T 1H3U 1H3V 1H3W 1H3Y 1HZH 1I7Z 1IIS 1IIX 1L6X 1N7M 1OQX 1T83 2IWG 2RCS
• Descriptor: IG GAMMA-1 CHAIN C REGION, IGM, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-beta-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[beta-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: autoimmune complex human igm rheumatoid factor igg1-fc, immunoglobulin c region, membrane, glycoprotein, transmembrane, hypothetical protein, immune system, immunoglobulin domain
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 6
• Total formula weight: 156036.73

Authors

Duquerroy, S.,Stura, E.A.,Bressanelli, S.,Browne, H.,Beale, D.,Hamon, M.,Casali, P.,Vaney, M.C.,Rey, F.A.,Sutton, B.J.,Taussig, M.J. (deposition date: 2006-09-28, release date: 2007-04-10, Last modification date: 2024-11-06)

Primary citation

Duquerroy, S.,Stura, E.A.,Bressanelli, S.,Fabiane, S.M.,Vaney, M.C.,Beale, D.,Hamon, M.,Casali, P.,Rey, F.A.,Sutton, B.J.,Taussig, M.J.
Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation.
J.Mol.Biol., 368:1321-1331, 2007

PubMed Abstract: Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of immunoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 A resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both Cgamma3 domains. A central role in the unusually hydrophilic epitope is played by the side-chain of Arg355, accounting for the subclass specificity of RF61, which recognizes IgG1,-2, and -3 in preference to IgG4, in which the corresponding residue is Gln355. Compared with a previously determined complex of a lower affinity RF (RF-AN) bound to IgG4 Fc, in which only residues at the very edge of the antibody combining site were involved in binding, the epitope bound by RF61 is centered in classic fashion on the axis of the V(H):V(L) beta-barrel. The complementarity determining region-H3 loop plays a key role, forming a pocket in which Arg355 is bound by two salt-bridges. The antibody contacts also involve two somatically mutated V(H) residues, reinforcing the suggestion of a process of antigen-driven maturation and selection for IgG Fc during the generation of this RF autoantibody.

PubMed: 17395205
DOI: 10.1016/j.jmb.2007.02.085

Experimental method

X-RAY DIFFRACTION (3 Å)