4x4m

Structure of FcgammaRI in complex with Fc reveals the importance of glycan recognition for high affinity IgG binding

spinqualitylabelsall models 4x4m, resolution 3.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4x4m is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.485Å Ligands: BMA, FUL, GAL, MAN, NAG, SIA 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. Function IGHG1_HUMAN Publication Abstract from PubMed Fc gamma receptor I (FcgammaRI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, FcgammaRI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human FcgammaRI in complex with the Fc domain of human IgG1. FcgammaRI binds to the Fc in a similar mode as the low-affinity FcgammaRII and FcgammaRIII receptors. In addition to many conserved contacts, FcgammaRI forms additional hydrogen bonds and salt bridges with the lower hinge region of Fc. Unique to the high-affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG loop, which enables a charged KHR motif to interact with proximal carbohydrate units of the Fc glycans. Both the length and the charge of the FcgammaRI FG loop are well conserved among mammalian species. Ala and Glu mutations of the FG loop KHR residues showed significant contributions of His-174 and Arg-175 to antibody binding, and the loss of the FG loop-glycan interaction resulted in an approximately 20- to 30-fold decrease in FcgammaRI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG1 resulted in a 40-fold loss in FcgammaRI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in FcgammaRI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target FcgammaRI for certain autoimmune diseases. Structure of FcgammaRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding.,Lu J, Chu J, Zou Z, Hamacher NB, Rixon MW, Sun PD Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):833-8. doi: 10.1073/pnas.1418812112., Epub 2015 Jan 5. PMID:25561553 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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