5d6d

Crystal structure of GASDALIE IgG1 Fc in complex with FcgRIIIa

spinqualitylabelsall models 5d6d, resolution 3.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5d6d is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, FUC, FUL, GAL, MAN, NAG Gene: IGHG1 (HUMAN), FCGR3A, CD16A, FCG3, FCGR3, IGFR3 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [IGHG1_HUMAN] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4. [FCG3A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Function [FCG3A_HUMAN] Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis. Publication Abstract from PubMed The Fc region of Immunoglobulin G (IgG) initiates inflammatory responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) through binding to activating Fc receptors (FcgammaRI, FcgammaRIIa, FcgammaRIIIa). These receptors are expressed on the surface of immune cells including macrophages, dendritic cells, and natural killer cells. An inhibitory receptor, FcgammaRIIb, is expressed on macrophages and other myeloid leukocytes simultaneously with the activating receptor FcgammaRIIa, thereby setting a threshold for cell activation. The affinity of IgG Fc for binding activating Fc receptors depends on IgG subclass and the composition of N-linked glycans attached to a conserved asparagine in the Fc CH2 domain. For example, Fc regions with afucosylated glycans bind more tightly to FcgammaRIIIa than fucosylated Fc, and afucosylated Fcs exhibit enhanced ADCC activity in vivo and in vitro. Enhanced pro-inflammatory responses have also been seen for Fc regions with amino acid substitutions. GASDALIE Fc is an Fc mutant (G236A/S239D/A330L/I332E) that exhibits a higher affinity for FcgammaRIIIa and increased effector functions in vivo compared to wild-type Fc. To explore its altered functions, we compared the affinities of GASDALIE and wild-type Fc for activating and inhibitory FcgammaRs. We also determined the crystal structure of GASDALIE Fc alone and bound to FcgammaRIIIa. The overall structure of GASDALIE Fc alone was similar to wild-type Fc structures, however, increased electrostatic interactions in the GASDALIE Fc:FcgammaRIIIa interface compared with other Fc:FcgammaR structures suggest a mechanism for the increased affinity of GASDALIE Fc for FcgammaRIIIa. Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcgammaRIIIa.,Ahmed AA, Keremane SR, Vielmetter J, Bjorkman PJ J Struct Biol. 2016 Apr;194(1):78-89. doi: 10.1016/j.jsb.2016.02.001. Epub 2016, Feb 2. PMID:26850169 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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