8dir

The complex structure between human IgG1 Fc and its high affinity receptor FcgRI H174R variant

spinqualitylabelsall models 8dir, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dir is a 3 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 2.3Å Ligands: BMA, FUC, GAL, MAN, NA, NAG 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 Understanding the molecular mechanism underlying the hierarchic binding between FcgammaRs and IgG antibodies is critical for therapeutic antibody engineering and FcgammaR functions. The recent determination of crystal structures of FcgammaRI-Fc complexes, however, resulted in two controversial mechanisms for the high affinity receptor binding to IgG. Here, we describe high resolution structures of a bovine FG-loop variant of FcgammaRI in complex with the Fc fragment of IgG(1) crystallized in three different conditions at neutral pH, confirming the characteristic FG loop-Fc interaction is critical to the high affinity immunoglobulin binding. We showed that the FcgammaRI D2-domain FG-loop functioned as a pH-sensing switch for IgG binding. Further live cell imaging of FcgammaRI-mediated internalization of immune complexes showed a pH sensitive temporal-spatial antibody-antigen uptake and release. Taken together, we demonstrate that the structures of FcgammaRI-Fc crystallized at neutral and acidic pH, respectively, represent the high and low affinity binding states of the receptor for IgG uptake and release. These results support a role for FcgammaRI in antigen delivery, highlight the importance of Fc glycan in antibody binding to the high affinity receptor and provide new insights to future antibody engineering. FcgammaRI FG-loop functions as a pH sensitive switch for IgG binding and release.,Lu J, Spencer M, Zou Z, Traver M, Brzostowski J, Sun PD Front Immunol. 2023 Feb 6;14:1100499. doi: 10.3389/fimmu.2023.1100499. , eCollection 2023. PMID:36814926 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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