Crystal structure and functional dissection of the cytostatic cytokine oncostatin M

Background: The cytokine oncostatin M (OSM) inhibits growth of certain tumo ur-derived cells, induces proliferation in other cell types (e.g. haemangio blasts) and is a mediator of inflammatory responses. Its mechanism of actio n is via specific binding to gp130 and either the leukaemia inhibitory fact or receptor (LIFR) or oncostatin M receptor (OSMR) systems at the cell surf ace to form an active signalling complex. Results: We report here the crystal structure of human oncostatin M (hOSM) along with mutagenesis data which map the receptor-binding epitopes of the molecule. The structure was determined to a resolution of 2.2 Angstrom and conforms to the haematopoietin cytokine up-up-down-down four-helix bundle t opology. The site 2 epitope, responsible for gp130 binding, is centred arou nd Gly120 which forms a 'dimple' on the surface of the molecule located on helices A and C. The site 3 motif, responsible for LIFR and OSMR binding, c onsists of a protruding Phe160/Lys163 pair located at the start of helix D. Conclusions: The data presented allow functional dissection of the receptor -binding interfaces to atomic resolution. Modelling suggests that the gp130 residue Phe169 packs into the site 2 dimple in an analogous fashion to str ucturally equivalent residues at the growth hormone-growth hormone receptor interface, implying that certain key features may underlie recognition acr oss the whole cytokine/receptor superfamily, Conversely, detailed compariso n of the available structures suggests that variations on a common theme di ctate the specificity of receptor-ligand interactions within the gp130 fami ly of cytokines.