8A8M

Structure of the MAPK p38alpha in complex with its activating MAP2K MKK6

Summary for 8A8M

• Entry DOI: 10.2210/pdb8a8m/pdb
• EMDB information: 15233
• Descriptor: Mitogen-activated protein kinase 14, Dual specificity mitogen-activated protein kinase kinase 6, PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, ... (4 entities in total)
• Functional Keywords: kinase, signalling, map kinase, phosphoryl transfer, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 86418.25

Authors

Bowler, M.W.,Juyoux, P.,Pellegrini, E. (deposition date: 2022-06-23, release date: 2022-07-13, Last modification date: 2024-11-13)

Primary citation

Juyoux, P.,Galdadas, I.,Gobbo, D.,von Velsen, J.,Pelosse, M.,Tully, M.,Vadas, O.,Gervasio, F.L.,Pellegrini, E.,Bowler, M.W.
Architecture of the MKK6-p38 alpha complex defines the basis of MAPK specificity and activation.
Science, 381:1217-1225, 2023

PubMed Abstract: 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.

PubMed: 37708276
DOI: 10.1126/science.add7859

Experimental method

ELECTRON MICROSCOPY (4 Å)