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-Structure paper
タイトル | Structural Investigations of Full-Length Insulin Receptor Dynamics and Signalling. |
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ジャーナル・号・ページ | J Mol Biol, Vol. 434, Issue 5, Page 167458, Year 2022 |
掲載日 | 2022年3月15日 |
著者 | Jeppe Nielsen / Jakob Brandt / Thomas Boesen / Tina Hummelshøj / Rita Slaaby / Gerd Schluckebier / Poul Nissen / |
PubMed 要旨 | Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs of binding sites 1 and 2. Here, we present cryo-EM studies of full-length human ...Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs of binding sites 1 and 2. Here, we present cryo-EM studies of full-length human insulin receptor (hIR) in an active state obtained at non-saturating, physiologically relevant insulin conditions. Insulin binds asymmetrically to the receptor under these conditions, occupying up to three of the four possible binding sites. Deletion analysis of the receptor together with site specific peptides and insulin analogs used in binding studies show that both sites 1 and 2 are required for high insulin affinity. We identify a homotypic interaction of the fibronectin type III domain (FnIII-3) of IR resulting in tight interaction of membrane proximal domains of the active, asymmetric receptor dimer. Our results show how insulin binding at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer. We propose an insulin binding and activation mechanism, which is sequential, exhibits negative cooperativity, and is based on asymmetry at physiological insulin concentrations with one to three insulin molecules activating IR. |
リンク | J Mol Biol / PubMed:35074483 |
手法 | EM (単粒子) |
解像度 | 6.7 - 9.1 Å |
構造データ | EMDB-13385, PDB-7pg0: EMDB-13386, PDB-7pg2: EMDB-13387, PDB-7pg3: EMDB-13388, PDB-7pg4: |
由来 |
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キーワード | MEMBRANE PROTEIN / Insulin / Receptor / Complex |