Efficiency of signalling through cytokine receptors depends critically on receptor orientation

Rashid S. Syed (), Scott W. Reid, Cuiwei Li, Janet C. Cheetham, Kenneth H. Aoki, Beishan Liu, Hangjun Zhan, Timothy D. Osslund, Arthur J. Chirino, Jiandong Zhang, Janet Finer-Moore, Steven Elliott, Karen Sitney, Bradley A. Katz, David J. Matthews, John J. Wendoloski, Joan Egrie and Robert M. Stroud
Additional contact information
Rashid S. Syed: Amgen Inc.
Scott W. Reid: Axys Pharmaceuticals Inc.
Cuiwei Li: Amgen Inc.
Janet C. Cheetham: Amgen Inc.
Kenneth H. Aoki: Amgen Inc.
Beishan Liu: Axys Pharmaceuticals Inc.
Hangjun Zhan: Axys Pharmaceuticals Inc.
Timothy D. Osslund: Amgen Inc.
Arthur J. Chirino: Amgen Inc.
Jiandong Zhang: Amgen Inc.
Janet Finer-Moore: University of California at San Francisco
Steven Elliott: Amgen Inc.
Karen Sitney: Amgen Inc.
Bradley A. Katz: Axys Pharmaceuticals Inc.
David J. Matthews: Axys Pharmaceuticals Inc.
John J. Wendoloski: Amgen Inc.
Joan Egrie: Amgen Inc.
Robert M. Stroud: Axys Pharmaceuticals Inc.

Nature, 1998, vol. 395, issue 6701, 511-516

Abstract: Abstract Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells1. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade2. The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM (ref. 3), 10−2 of its K d value for erythropoietin–EPOR binding site 1 (Kd ≈ 1 nM), and 10−5 of the K d for erythropoietin–EPOR binding site 2 (Kd ≈ 1 μM)4. Overall half-maximal binding (IC50) of cell-surface receptors is produced with ∼0.18 nM erythropoietin, indicating that only ∼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 responses5,6 but much less efficiently, requiring concentrations close to their K d values (∼0.1 μM). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Å from two crystal forms, shows that erythropoietin imposes a unique 120° angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.

Date: 1998
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DOI: 10.1038/26773

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