4C55: Crystal Structure Of Serum-derived Human Igg4 Fc

Citation:
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 FcgammaRII and FcgammaRIII, 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 2.35A, 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 FcgammaRII, FcgammaRIII 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.
PDB ID: 4C55Download
MMDB ID: 115058
PDB Deposition Date: 2013/9/10
Updated in MMDB: 2013/11
Experimental Method:
x-ray diffraction
Resolution: 2.35  Å
Source Organism:
Similar Structures:
Biological Unit for 4C55: monomeric; determined by author and by software (PISA)
Molecular Components in 4C55
Label Count Molecule
Protein (1 molecule)
1
IG Gamma-4 Chain C Region(Gene symbol: IGHG4)
Molecule annotation
Chemicals (11 molecules)
1
3
2
1
3
2
4
1
5
1
6
1
7
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.