Atomic structure of the GCSF–receptor complex showing a new cytokine–receptor recognition scheme

Aritomi, Masaharu; Kunishima, N.; Okamoto, Tamotsu; Kuroki, Ryota; Ota, Yusuke; Morikawa, Kosuke

doi:10.1038/44394

Cited by 140 publications

(95 citation statements)

References 28 publications

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“…2), with additional potentially important contacts in the loop regions. The recently reported crystal structure of G-CSF complexed with the cytokine receptor homologous region of the G-CSF receptor reinforces the importance of these helices and suggests additional contacts by residues in the N-terminal region of G-CSF, which is unstructured in the unbound protein (19).…”

mentioning

confidence: 83%

Reengineering Granulocyte Colony-stimulating Factor for Enhanced Stability

Bishop¹,

Koay²,

Sartorelli³

et al. 2001

Journal of Biological Chemistry

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Granulocyte colony-stimulating factor is a longchain cytokine that has both biological and therapeutic applications. It is involved in the production and maturation of neutrophilic progenitor cells and neutrophils and is administered to stimulate the production of white blood cells to reduce the risk of serious infection in immunocompromised patients. We have reengineered granulocyte colony-stimulating factor to improve the thermodynamic stability of the protein, focusing on enhancing the ␣-helical propensity of residues in the antiparallel 4-helix bundle of the protein. These redesigns resulted in proteins with substantially enhanced stability while retaining wild-type levels of biological activity, measured as the ability of the reengineered proteins to stimulate the proliferation of murine myeloid cells transfected with the granulocyte colony-stimulating factor receptor.

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confidence: 83%

Reengineering Granulocyte Colony-stimulating Factor for Enhanced Stability

Bishop¹,

Koay²,

Sartorelli³

et al. 2001

Journal of Biological Chemistry

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“…Because both receptors were shown to exist as homodimers (34 -37), ligand binding most likely only activates the receptor without modifying receptor dimerization. In the 2:2 complex of granulocyte colony-stimulating factor-granulocyte colony-stimulating factor receptor (38), each ligand binds both receptors, but there are no contacts between the two ligands or the two receptor fragments, suggesting that receptor dimerization is a consequence of ligand binding. In the specific case of the OB-R, a 2:2 complex of leptin and the extracellular domain of OB-R has been reported (15,39), but the relationship between receptor dimerization and activation remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Leptin Receptor by a Ligand-induced Conformational Change of Constitutive Receptor Dimers

Couturier¹,

Jockers

2003

Journal of Biological Chemistry

116

113

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Binding of leptin to the leptin receptor is crucial for body weight and bone mass regulation in mammals. Leptin receptors were shown to exist as dimers, but the role of dimerization in receptor activation remains unknown. Using a quantitative Bioluminescence Resonance Energy Transfer approach, we show here in living cells that ϳ60% of the leptin receptor exists as constitutive dimers at physiological expression levels in the absence of leptin. No further increase in leptin receptor dimerization was detected in the presence of leptin. Importantly, in cells expressing the short leptin receptor isoform, leptin promoted a robust enhancement of energy transfer signals that reflect specific conformational changes of pre-existing leptin receptor dimers and that may be used as read-out in screening assays for leptin receptor ligands. Both leptin receptor dimerization and the leptin-induced energy transfer were Janus kinase 2-independent. Taken together, our data support a receptor activation model based on ligand-induced conformational changes rather than ligand-induced dimerization.

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“…The crystal structure of a 2:2 complex between human GCSF (hGCSF) and the CRH domain of mouse GCSF-R has been reported (11). Although this structure provided important details of ligand-receptor interactions, it was not able to clearly elucidate the activation mechanism of GCSF-R because the complex did not include the natural Ig-like domain with high affinity for ligand (12).…”

mentioning

confidence: 99%

Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

Tamada

Honjo²,

Maeda³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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117

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A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (GCSF) and a ligand binding region of GCSF receptor (GCSF-R), has been determined to 2.8 Å resolution. The GCSF:GCSF-R complex formed a 2:2 stoichiometry by means of a cross-over interaction between the Ig-like domains of GCSF-R and GCSF. The conformation of the complex is quite different from that between human GCSF and the cytokine receptor homologous domain of mouse GCSF-R, but similar to that of the IL-6͞gp130 signaling complex. The Ig-like domain cross-over structure necessary for GCSF-R activation is consistent with previously reported thermodynamic and mutational analyses.ligand-receptor interaction ͉ x-ray crystallography ͉ IL-6 ͉ gp130

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Atomic structure of the GCSF–receptor complex showing a new cytokine–receptor recognition scheme

Cited by 140 publications

References 28 publications

Reengineering Granulocyte Colony-stimulating Factor for Enhanced Stability

Reengineering Granulocyte Colony-stimulating Factor for Enhanced Stability

Activation of the Leptin Receptor by a Ligand-induced Conformational Change of Constitutive Receptor Dimers

Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

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