| Literature DB >> 29247053 |
James I Robinson1,2, Euan W Baxter1,2, Robin L Owen3, Maren Thomsen4, Darren C Tomlinson4,5, Mark P Waterhouse1,2, Stephanie J Win1,2, Joanne E Nettleship6,7, Christian Tiede5, Richard J Foster4,8, Raymond J Owens6,7, Colin W G Fishwick4,8, Sarah A Harris4,9, Adrian Goldman5,10, Michael J McPherson11,5, Ann W Morgan12,2.
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.Entities:
Keywords: Affimer; Fc gamma receptor IIIa; allosteric; competitive; specific inhibitor
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Year: 2017 PMID： 29247053 PMCID： PMC5776790 DOI： 10.1073/pnas.1707856115
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205