Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Export

@article{citeulike:2859280, abstract = {Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM, 10(-2) of its Kd value for erythropoietin-EPOR binding site 1 (Kd approximately equal to nM), and 10(-5) of the Kd for erythropoietin-EPOR binding site 2 (Kd approximately equal to 1 microM). Overall half-maximal binding (IC50) of cell-surface receptors is produced with approximately 0.18 nM erythropoietin, indicating that only approximately 6\% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses but much less efficiently, requiring concentrations close to their Kd values (approximately 0.1 microM). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 A from two crystal forms, shows that erythropoietin imposes a unique 120 degrees angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.}, address = {Amgen Inc., Thousand Oaks, California 91320-1789, USA. rsyed@amgen.com}, author = {Syed, R. S. and Reid, S. W. and Li, C. and Cheetham, J. C. and Aoki, K. H. and Liu, B. and Zhan, H. and Osslund, T. D. and Chirino, A. J. and Zhang, J. and Finer-Moore, J. and Elliott, S. and Sitney, K. and Katz, B. A. and Matthews, D. J. and Wendoloski, J. J. and Egrie, J. and Stroud, R. M.}, citeulike-article-id = {2859280}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/26773}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/9774108}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=9774108}, day = {1}, doi = {10.1038/26773}, issn = {0028-0836}, journal = {Nature}, keywords = {erythropoitein}, month = {October}, number = {6701}, pages = {511--516}, posted-at = {2008-06-03 15:50:14}, priority = {2}, title = {Efficiency of signalling through cytokine receptors depends critically on receptor orientation.}, url = {http://dx.doi.org/10.1038/26773}, volume = {395}, year = {1998} }

TY - JOUR ID - citeulike:2859280 L3 - citeulike-article-id:2859280 N2 - Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM, 10(-2) of its Kd value for erythropoietin-EPOR binding site 1 (Kd approximately equal to nM), and 10(-5) of the Kd for erythropoietin-EPOR binding site 2 (Kd approximately equal to 1 microM). Overall half-maximal binding (IC50) of cell-surface receptors is produced with approximately 0.18 nM erythropoietin, indicating that only approximately 6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses but much less efficiently, requiring concentrations close to their Kd values (approximately 0.1 microM). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 A from two crystal forms, shows that erythropoietin imposes a unique 120 degrees angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways. IS - 6701 JF - Nature SN - 0028-0836 AD - Amgen Inc., Thousand Oaks, California 91320-1789, USA. rsyed@amgen.com EP - 516 TI - Efficiency of signalling through cytokine receptors depends critically on receptor orientation. VL - 395 SP - 511 KW - erythropoitein AU - Syed, RS AU - Reid, SW AU - Li, C AU - Cheetham, JC AU - Aoki, KH AU - Liu, B AU - Zhan, H AU - Osslund, TD AU - Chirino, AJ AU - Zhang, J AU - Finer-Moore, J AU - Elliott, S AU - Sitney, K AU - Katz, BA AU - Matthews, DJ AU - Wendoloski, JJ AU - Egrie, J AU - Stroud, RM PY - 1998/10/01/ UR - http://dx.doi.org/10.1038/26773 ER -