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Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action

DOI: 10.1073/pnas.1707856115 DOI Help

Authors: James I. Robinson (University of Leeds; National Institute of Health Research-Leeds Biomedical Research Centre) , Euan W. Baxter (University of Leeds; National Institute of Health Research-Leeds Biomedical Research Centre) , Robin L. Owen (Diamond Light Source) , Maren Thomsen (University of Leeds) , Darren C. Tomlinson (University of Leeds) , Mark P. Waterhouse (University of Leeds; National Institute of Health Research-Leeds Biomedical Research Centre) , Stephanie J. Win (University of Leeds; National Institute of Health Research-Leeds Biomedical Research Centre) , Joanne E. Nettleship (Oxford Protein Production Facility-United Kingdom Research Complex at Harwell; Wellcome Trust Centre for Genomic Medicine, Oxford University) , Christian Tiede (University of Leeds) , Richard J. Foster (Astbury Centre for Structural and Molecular Biology, University of Leeds) , Raymond J. Owens (Oxford Protein Production Facility-United Kingdom Research Complex at Harwell; Wellcome Trust Centre for Genomic Medicine, Oxford University) , Colin W. G. Fishwick (Astbury Centre for Structural and Molecular Biology, University of Leeds) , Sarah A. Harris (Astbury Centre for Structural and Molecular Biology, University of Leeds) , Adrian Goldman (University of Leeds; University of Helsinki) , Michael J. Mcpherson (University of Leeds) , Ann W. Morgan (University of Leeds; National Institute of Health Research-Leeds Biomedical Research Centre)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 115 , PAGES E72 - E81

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 5969

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.

Journal Keywords: Fc gamma receptor IIIa; specific inhibitor; Affimer; allosteric; competitive

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography