1998
DOI: 10.1038/2965
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An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation

Abstract: Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 A resolution has unexpectedly revealed that dimerization still occurs, but the orientation between receptor molecules is altered relative to active (agonist) peptide complexes. Comparison … Show more

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Cited by 212 publications
(154 citation statements)
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“…It may also be possible to mutagenize TC2-3 to identify essential structural features; optimize its affinity or specificity; or fine-tune its activity. It may also be possible to isolate inhibitory derivatives of TC2-3 that force the hEPOR dimer to adopt a non-productive orientation, as has been reported for a peptide that binds to the extracellular domain of the hEPOR (24). Finally, traptamers may also serve as structurally simple templates that can inform the design of peptide or peptidomimetic reagents and drugs that specifically modulate a wide variety of cellular and viral transmembrane protein targets.…”
Section: Discussionmentioning
confidence: 99%
“…It may also be possible to mutagenize TC2-3 to identify essential structural features; optimize its affinity or specificity; or fine-tune its activity. It may also be possible to isolate inhibitory derivatives of TC2-3 that force the hEPOR dimer to adopt a non-productive orientation, as has been reported for a peptide that binds to the extracellular domain of the hEPOR (24). Finally, traptamers may also serve as structurally simple templates that can inform the design of peptide or peptidomimetic reagents and drugs that specifically modulate a wide variety of cellular and viral transmembrane protein targets.…”
Section: Discussionmentioning
confidence: 99%
“…These findings imply that the nonfunctional W282R mutant must alter either the relative orientations of the receptor cytoplasmic regions or the alignment of JAK2 molecules in the receptor dimer. In addition, EPO-mimetic peptides that bind to and dimerize the EPOR extracellular domain are not always sufficient to activate intracellular signal transduction (53). Thus, it appears that JAK2 molecules and/or the cytoplasmic regions of the EPOR must be brought into the correct orientation in the receptor dimer to create a competent, activated receptor complex.…”
Section: Discussionmentioning
confidence: 99%
“…For instance, if we take at face value what we have already learned about the EPO antibody that has full agonist activity, it appears to require cooperativity of two different binding specificities whose agonist mechanism is similar to the asymmetric interaction of EPO with the EpoR (14). Thus, the fact that antibodies with either specificity can bind to EpoR, but only act as potent agonists when they are combined in the same molecule, suggests that simple dimerization of the EpoR is not sufficient for activity, or their dimer configurations are more similar to partial agonists (16), antagonists (19), or unliganded dimers (17,18) (Fig. 6).…”
Section: Discussionmentioning
confidence: 99%
“…One homodimeric antibody is only a partial agonist, which suggests a more symmetric interaction with less activation as for a peptide agonist (16). Antibodies that bind EpoR, but do not activate, likely bind to only one arm of the EpoR unliganded dimer (17)(18)(19) in an orientation that precludes bivalent association of the antibody. dimers, they could not replicate the mechanism of authentic EPO that requires asymmetric binding and, as seen here for homodimeric molecules, their best antibody from the screening had only about 60% of the activity of authentic EPO.…”
Section: Discussionmentioning
confidence: 99%
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