8U8J

Co-crystal structure of phosphorylated ERK2 in complex with ERK1/2 inhibitor #16

Summary for 8U8J

• Entry DOI: 10.2210/pdb8u8j/pdb
• Related: 8U8K
• Descriptor: Mitogen-activated protein kinase 1, (4M)-4-{(4R)-3-[(2S)-2-methylbutyl][1,2,4]triazolo[4,3-a]pyridin-7-yl}-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine (3 entities in total)
• Functional Keywords: protein kinase, atp-competitive inhibitor, conformation selection, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41496.46

Authors

Anderson, J.W.,Vigers, G.P. (deposition date: 2023-09-18, release date: 2024-03-27, Last modification date: 2024-10-23)

Primary citation

Anderson, J.W.,Vaisar, D.,Jones, D.N.,Pegram, L.M.,Vigers, G.P.,Chen, H.,Moffat, J.G.,Ahn, N.G.
Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2.
Elife, 12:-, 2024

PubMed Abstract: Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named 'L' and 'R,' where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here, we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the +1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

PubMed: 38537148
DOI: 10.7554/eLife.91507

Experimental method

X-RAY DIFFRACTION (2.1 Å)