Robinson, JI orcid.org/0000-0001-5425-7520, Baxter, EW, Owen, RL et al. (13 more authors) (2018) Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action. Proceedings of the National Academy of Sciences, 115 (1). E72-E81. ISSN 0027-8424
Abstract
Protein–protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcγRs). High sequence identity (98%) between the genes encoding FcγRIIIa (expressed on macrophages and natural killer cells) and FcγRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcγRIIIa-specific artificial binding proteins called “Affimer” that block IgG binding and abrogate FcγRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The Authors. This is an author produced version of a paper published in Proceedings of the National Academy of Sciences. Uploaded in accordance with the publisher's self-archiving policy. In order to comply with the publisher requirements the University does not require the author to sign a nonexclusive licence for this paper. |
Keywords: | Fc gamma receptor IIIa; specific inhibitor; Affimer; allosteric; competitive |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Synthetic Biology (Leed) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Physics and Astronomy (Leeds) > Theoretical Physics (Leeds) |
Funding Information: | Funder Grant number Arthritis Research UK 19764 |
Depositing User: | Symplectic Publications |
Date Deposited: | 20 Dec 2017 14:21 |
Last Modified: | 16 Dec 2024 13:36 |
Status: | Published |
Publisher: | National Academy of Sciences |
Identification Number: | 10.1073/pnas.1707856115 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125416 |