期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 426, 期 8, 页码 1799-1811出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2014.01.011
关键词
glycoprotein; N-glycan; molecular dynamics; x-ray crystallography
资金
- National Institutes of Health [K22AI099165, R01GM033225, P41GM103390]
- National Science Foundation (NSF) [NSF1148276]
- CUDA fellowship, NVIDIA Inc.
- NSF [TG-MCB090110]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology at Iowa State University
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [1148276] Funding Source: National Science Foundation
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 gamma receptors (Fc gamma 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 gamma 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 gamma 2 domains and N-glycan than previously observed. Residues in the C gamma 2/C gamma 3 interface and disulfide-bonded hinge were identified as influencing the C gamma 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 gamma Rs interconverted with Fc conformations distinct from those observed in Fc gamma R complexes, which may represent a transient, nonbinding population. (C) 2014 Elsevier Ltd. All rights reserved.
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