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Determination of the human type I interferon receptor binding site on human interferon-2 by cross saturation and an NMR-based model of the complex

Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel

(RECEIVED April 11, 2006; FINAL REVISION August 7, 2006; ACCEPTED August 12, 2006)

Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of cancer, hepatitis C, and multiple sclerosis. All type I IFNs bind to a cell surface receptor consisting of two subunits, IFNAR1 and IFNAR2, associating upon binding of interferon. The structure of the extracellular domain of IFNAR2 (R2-EC) was solved recently. Here we study the complex and the binding interface of IFN2 with R2-EC using multidimensional NMR techniques. NMR shows that IFN2 does not undergo significant structural changes upon binding to its receptor, suggesting a lock-and-key mechanism for binding. Cross saturation experiments were used to determine the receptor binding site upon IFN2. The NMR data and previously published mutagenesis data were used to derive a docking model of the complex with an RMSD of 1 Å, and its well-defined orientation between IFN2 and R2-EC and the structural quality greatly improve upon previously suggested models. The relative ligand–receptor orientation is believed to be important for interferon signaling and possibly one of the parameters that distinguish the different IFN I subtypes. This structural information provides important insight into interferon signaling processes and may allow improvement in the development of therapeutically used IFNs and IFN-like molecules.

Keywords: interferons; protein–protein docking; protein–protein interactions; multidimensional NMR; cross saturation

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