5MN2

Cocrystal structure of Fc gamma receptor IIIa interacting with Affimer G3, a specific binding protein which blocks IgG binding to the receptor.

Summary for 5MN2

• Entry DOI: 10.2210/pdb5mn2/pdb
• Descriptor: Low affinity immunoglobulin gamma Fc region receptor III-A, Affimer G3, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: fc gamma receptor iiia affimer allosteric inhibitor fcgr3a, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 65242.10

Authors

Robinson, J.I.,Owen, R.L.,Tomlinson, D.C.,Baxter, E.W.,Nettleship, J.E.,Waterhouse, M.P.,Harris, S.A.,Owens, R.J.,McPherson, M.J.,Morgan, A.W.,Tiede, C.,Goldman, A.,Thomsen, M. (deposition date: 2016-12-12, release date: 2017-12-13, Last modification date: 2024-11-13)

Primary citation

Robinson, J.I.,Baxter, E.W.,Owen, R.L.,Thomsen, M.,Tomlinson, D.C.,Waterhouse, M.P.,Win, S.J.,Nettleship, J.E.,Tiede, C.,Foster, R.J.,Owens, R.J.,Fishwick, C.W.G.,Harris, S.A.,Goldman, A.,McPherson, M.J.,Morgan, A.W.
Affimer proteins inhibit immune complex binding to Fc gamma RIIIa with high specificity through competitive and allosteric modes of action.
Proc. Natl. Acad. Sci. U.S.A., 115:E72-E81, 2018

PubMed 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.

PubMed: 29247053
DOI: 10.1073/pnas.1707856115

Experimental method

X-RAY DIFFRACTION (2.35 Å)