期刊
PROTEIN SCIENCE
卷 17, 期 11, 页码 1894-1906出版社
WILEY
DOI: 10.1110/ps.036624.108
关键词
proteins of the immune system; structure; computational analysis of protein structure; molecular mechanics/dynamics; thermodynamics; hydrodynamics; complement; Efb-C; electrostatics
资金
- U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- Southeast Regional Collaborative Access Team (SER-CAT)
- Argonne National Laboratory
- National Institutes of Health [GM078988, AI071028, P01AI68730]
- National Science Foundation [0523908, CNS-0421109, CNS-0454333]
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [0523908] Funding Source: National Science Foundation
The C3-inhibitory domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb-C) defines a novel three-helix bundle motif that regulates complement activation. Previous crystallographic studies of Efb-C bound to its cognate subdomain of human C3 (C3d) identified Arg-131 and Asn-138 of Efb-C as key residues for its activity. In order to characterize more completely the physical and chemical driving forces behind this important interaction, we employed in this study a combination of structural, biophysical, and computational methods to analyze the interaction of C3d with Efb-C and the single-point mutants R131A and N138A. Our results show that while these mutations do not drastically affect the structure of the Efb-C/C3d recognition complex, they have significant adverse effects on both the thermodynamic and kinetic profiles of the resulting complexes. We also characterized other key interactions along the Efb-C/C3d binding interface and found an intricate network of salt bridges and hydrogen bonds that anchor Efb-C to C3d, resulting in its potent complement inhibitory properties.
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