4C55

Crystal structure of serum-derived human IgG4 Fc

Summary for 4C55

• Entry DOI: 10.2210/pdb4c55/pdb
• Related: 4C54
• Descriptor: IG GAMMA-4 CHAIN C REGION, 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)-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, 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)-alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: immune system, igg, antibody, immunoglobulin, igg1
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P01861
• Total number of polymer chains: 2
• Total formula weight: 52966.99

Authors

Davies, A.M.,Rispens, T.,Ooijevaar-deHeer, P.,Gould, H.J.,Jefferis, R.,Aalberse, R.C.,Sutton, B.J. (deposition date: 2013-09-10, release date: 2013-11-13, Last modification date: 2023-12-20)

Primary citation

Davies, A.M.,Rispens, T.,Ooijevaar-Deheer, P.,Gould, H.J.,Jefferis, R.,Aalberse, R.C.,Sutton, B.J.
Structural Determinants of Unique Properties of Human Igg4-Fc
J.Mol.Biol., 426:630-, 2014

PubMed Abstract: Human IgG4, normally the least abundant of the four subclasses of IgG in serum, displays a number of unique biological properties. It can undergo heavy-chain exchange, also known as Fab-arm exchange, leading to the formation of monovalent but bispecific antibodies, and it interacts poorly with FcγRII and FcγRIII, and complement. These properties render IgG4 relatively "non-inflammatory" and have made it a suitable format for therapeutic monoclonal antibody production. However, IgG4 is also known to undergo Fc-mediated aggregation and has been implicated in auto-immune disease pathology. We report here the high-resolution crystal structures, at 1.9 and 2.35 Å, respectively, of human recombinant and serum-derived IgG4-Fc. These structures reveal conformational variability at the CH3-CH3 interface that may promote Fab-arm exchange, and a unique conformation for the FG loop in the CH2 domain that would explain the poor FcγRII, FcγRIII and C1q binding properties of IgG4 compared with IgG1 and -3. In contrast to other IgG subclasses, this unique conformation folds the FG loop away from the CH2 domain, precluding any interaction with the lower hinge region, which may further facilitate Fab-arm exchange by destabilisation of the hinge. The crystals of IgG4-Fc also display Fc-Fc packing contacts with very extensive interaction surfaces, involving both a consensus binding site in IgG-Fc at the CH2-CH3 interface and known hydrophobic aggregation motifs. These Fc-Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen.

PubMed: 24211234
DOI: 10.1016/J.JMB.2013.10.039

Experimental method

X-RAY DIFFRACTION (2.35 Å)