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-Structure paper
タイトル | Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation. |
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ジャーナル・号・ページ | Science, Vol. 381, Issue 6663, Page 1217-1225, Year 2023 |
掲載日 | 2023年9月15日 |
著者 | Pauline Juyoux / Ioannis Galdadas / Dorothea Gobbo / Jill von Velsen / Martin Pelosse / Mark Tully / Oscar Vadas / Francesco Luigi Gervasio / Erika Pellegrini / Matthew W Bowler / |
PubMed 要旨 | The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the ...The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo-electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase. |
リンク | Science / PubMed:37708276 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.422 - 4.0 Å |
構造データ | EMDB-15233, PDB-8a8m: PDB-5etc: PDB-5eti: |
化合物 | ChemComp-SO4: ChemComp-HOH: ChemComp-AP2: ChemComp-MG: |
由来 |
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キーワード | TRANSFERASE / MAPK14 / inactive kinase / activation loop / MAPK / dead kinase / p38 / IMMUNE SYSTEM / Kinase / Signalling / MAP kinase / phosphoryl transfer |