Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 Å

Livnah, Oded; Stura, E.A.; Johnson, Dana L.; Middleton, Steven A.; Mulcahy, Linda S.; Wrighton, Nicholas C.; Dower, William J.; Jolliffe, Linda K.; Wilson, Ian A.

doi:10.1126/science.273.5274.464

Cited by 588 publications

(463 citation statements)

References 61 publications

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“…This assumes that the receptors follow the structural pattern that has been observed in the GHR, PRLR, and EpoR, the class 1 cytokine receptors for which structures are known (de Vos et al, 1992;Livnah et al, 1996). For IL-6 and CNTF, such a three-site cytokine/receptor binding model is consistent with mutagenesis data and the finding that the ternary receptor-complexes of IL-6 (Ward et al, 1994b;Paonessa et al, 1995) and CNTF are hexameric (cf.…”

Section: The Complex Of Growth Hormone and Its Receptorsupporting

confidence: 54%

“…The structures of the class I cytokine receptors solved to date, GHR (de Vos et al, 1992), PRLR , and EpoR (Livnah et al, 1996) all show an angle of -90' between the two FN 111 domains of the CBD. Although there is a slight variation in the orientation of the two FN 111 domains in the CBDs relative to one another (a translation of 2-5 8, and a rotation of 8-12') (Livnah et al, 1996;Wells and de Vos, 1996), the receptors bind their ligands through the same loop regions (Livnah et al ., 1996). There is a similar conservation of the angle between the two FN 111 domains of the binding domain in the (Hibi et al, 1990).…”

Section: The High Affinity Ternary Il-6 Receptor-complex Is a Hexamermentioning

confidence: 96%

“…McKay, 1992 Feng et al, 1996Redfield et al, 1994Powers et al, 1992, 1993Muller et al, 1994Walter et al, 1992aWlodawer et al, 1992Muller et al, 1995Walter et al, 1992bRozwarski et al, 1996Milburn et al, 1993Pandit et al, 1992Hill et al, 1993Zink et al, 1994Lovejoy et al, 1993Lovejoy et al, 1993Lovejoy et al, 1993Robinson et al, 1994de Vos et al, 1992Ultsch et al, 1994Somers et al, 1994Sundstrom et al, 1996Sundstrom et al, 1996 Chantalat et aLc Abdel-Meguid et al, 1987McDonald et al, 1995Walter & Nagahhushan, 1995Zdanov et al, 1996Radhakrishnan et al, 1996Senda et al, 1995Ealick et al, 1991Samudzi et al, 1991Samudzi & Rubin, 1993Livnah et al, 1996de Vos et al, 1992Sundstrom et al, 1996Sundstrom et al, 1996Somers et al, 1994Harlos et al, 1994Muller et al, 1996Banner et al. 1996 "Cytokine or receptor class is shown along with the method of structure determination and resolution where appropriate.…”

Section: Il-6 and Helical Cytokine Structurementioning

confidence: 99%

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Interleukin‐6: Structure‐function relationships

et al. 1997

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Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

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Section: The Complex Of Growth Hormone and Its Receptorsupporting

confidence: 54%

Section: The High Affinity Ternary Il-6 Receptor-complex Is a Hexamermentioning

confidence: 96%

Section: Il-6 and Helical Cytokine Structurementioning

confidence: 99%

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Interleukin‐6: Structure‐function relationships

et al. 1997

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“…Structural and biochemical analyses have demonstrated that epo induces receptor dimerization (Barber et al, 1994;Livnah et al, 1996;Matthews et al, 1996;Watowich et al, 1992Watowich et al, , 1994. The dominant action of mutant receptors in J2E cells suggests that they heterodimerize with wild type receptors upon ligand binding, thereby altering normal receptor function.…”

Section: Discussionmentioning

confidence: 99%

Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo

et al. 2000

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J2E cells produce rapid, fatal erythroleukemias in vivo but still respond to erythropoietin (epo) in vitro by di erentiating, proliferating and remaining viable in the absence of serum. Mutant epo receptors were introduced into these cells to determine whether they could in¯uence the di erent biological responses to epo in vitro and the development of erythroleukemias. Three mutant receptors were used as cytoplasmic truncation mutants D257 and D321 (above box 1 and below box 2 respectively), and the cytoplasmic point mutant W282R (defective for JAK2 activation). Strikingly, the D321 mutation produced a hyper-sensitive response in vitro to epoinduced di erentiation and viability, but not to proliferation. In contrast with the D321 receptor, the D257 and W282R mutants inhibited all biological responses to epo due to impaired JAK2 phosphorylation. Signi®cantly, erythroleukemias took almost twice as long to develop with cells containing the W282R mutation, indicating that JAK2 plays an important role in the emergence of these leukemias. These data demonstrate that mutant epo receptors dominantly altered responses of J2E cells to epo in culture and the development of erythroleukemias. Oncogene (2000) 19, 953 ± 960.

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“…4c). The WSXWS motif is found in class 1 cytokine receptors [156]. In IL-10R1, the HSQWT sequence divides the G strand of D1 domain in two equivalent sub-parts, named G1 and G2 [117].…”

Section: The Il-22/il-22bp Structure and Interfacesmentioning

confidence: 99%

Structure and function of interleukin-22 and other members of the interleukin-10 family

Trivella

Ferreira-Junior

Dumoutier

et al. 2010

Cell. Mol. Life Sci.

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The IL-10 family of cytokines is comprised of IL-10, . The IL-10 family members bind to shared class II cytokine receptor chains that associate in various combinations in heterodimeric complexes. Upon interleukin/receptor complex formation, these proteins switch on the Jak/STAT pathway and elicit pleiotropic biological responses whose variety sharply contrasts with their structural similarities. IL-10 family members are involved in several human diseases and health conditions and hence their structural analyses may provide valuable information to design specific therapeutic strategies. In this review, we describe the human interleukin-10 family of cytokines, focusing on their structures and functions, with particular attention given to IL-22 and IL-10. We report on the recently published structures of IL-10 cytokine family members and their complexes with cognate transmembrane and soluble receptors as well as on interleukin physiology and physiopathology.

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Functional Mimicry of a Protein Hormone by a Peptide Agonist: The EPO Receptor Complex at 2.8 Å

Cited by 588 publications

References 61 publications

Interleukin‐6: Structure‐function relationships

Interleukin‐6: Structure‐function relationships

Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo

Structure and function of interleukin-22 and other members of the interleukin-10 family

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