title: Discovery and characterization of cooperative ligand binding in the adaptive region of interleukin-2.
abstract: The cytokine hormone interleukin-2 (IL-2) contains a highly adaptive region that binds small, druglike molecules. The binding properties of this adaptive region have been explored using a "tethering" method that relies on the formation of a disulfide bond between the protein and small-molecule ligands. Using tethering, surface plasmon resonance (SPR), and X-ray crystallography, we have discovered that the IL-2 adaptive region contains at least two cooperative binding sites where the binding of a first ligand to one site promotes or antagonizes the binding of a second ligand to the second site. Cooperative energies of interaction of -2 kcal/mol are observed. The observation that the adaptive region contains two adjacent sites may lead to the development of tight-binding antagonists of a protein-protein interaction. Cooperative ligand binding in the adaptive region of IL-2 underscores the importance of protein dynamics in molecular recognition. The tethering approach provides a novel and general strategy for discovering such cooperative binding interactions in specific, flexible regions of protein structure.
authors.affiliation: Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hyde
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Braisted
authors.forename: Mike
authors.initials: M
authors.lastname: Randal
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D001671:Biochemistry / Q000379:methods; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D004220:Disulfides; D007376:Interleukin-2; D008024:Ligands; D003545:Cysteine