Immunoglobulin G1 Fc Domain Motions: Implications for Fc Engineering

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• 作者：Martin Frank¹ ; Ross C. Walker² ; ³ ; William N. Lanzilotta⁴ ; James H. Prestegard⁵ ; Adam W. Barb⁶ ; ^{abarb@iastate.edu" class="auth_mail}
• 关键词：Fc ; fragment crystallizable ; Fc纬R ; Fc纬 receptor ; MD ; molecular dynamics ; PEG ; polyethylene glycol ; PDB ; Protein Data Bank ; wt ; wild type
• 刊名：Journal of Molecular Biology
• 出版年：17 April, 2014
• 年：2014
• 卷：426
• 期：8
• 页码：1799-1811
• 全文大小：2037 K

文摘

The fragment crystallizable (Fc) region links the key pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fc纬 receptors (Fc纬Rs) on immune cells. The cellular response and committal to a damaging, though protective, immune response are tightly controlled at multiple levels. Control mechanisms are diverse and in many cases unclear, but one frequently suggested contribution originates in Fc纬R affinity being modulated through shifts in Fc conformational sampling. Here, we report a previously unseen IgG1 Fc conformation. This observation motivated an extensive molecular dynamics investigation of polypeptide and glycan motions that revealed greater amplitude of motion for the N-terminal C纬2 domains and N-glycan than previously observed. Residues in the C纬2/C纬3 interface and disulfide-bonded hinge were identified as influencing the C纬2 motion. Our results are consistent with a model of Fc that is structurally dynamic. Conformational states that are competent to bind immune-stimulating Fc纬Rs interconverted with Fc conformations distinct from those observed in Fc纬R complexes, which may represent a transient, nonbinding population.