ArticleProceedings of the National Academy of Sciences of the United States of America2019
Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed, 47 citations in OpenAlex.
- Tyrosine kinases sample unique activation ensembles.bioRxiv : the preprint server for biology · 2026Article
- ERK autoinhibition mechanism informs a drug combination strategy.Protein science : a publication of the Protein Society · 2026Article
- ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events.Journal of molecular biology · 2025Article
- PD-L1/PD-1 checkpoint pathway regulates astrocyte morphogenesis and myelination during brain development.Molecular psychiatry · 2025Article
- A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.Signal transduction and targeted therapy · 2025Article
- Dual-action kinase inhibitors influence p38α MAP kinase dephosphorylation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- Dual-Action Kinase Inhibitors Influence p38α MAP Kinase Dephosphorylation.bioRxiv : the preprint server for biology · 2024Article
- Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2.eLife · 2024Article
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2.bioRxiv : the preprint server for biology · 2023Article
- Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β.Nature communications · 2023Article
- Quantitative Structural Proteomics Unveils the Conformational Changes of Proteins under the Endoplasmic Reticulum Stress.Analytical chemistry · 2022Article
- Divergent kinase WNG1 is regulated by phosphorylation of an atypical activation sub-domain.The Biochemical journal · 2022Article
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Network pharmacology and experimental verification based research into the effect and mechanism of Aucklandiae Radix-Amomi Fructus against gastric cancer.Scientific reports · 2022Article
- The Two Non-Visual Arrestins Engage ERK2 Differently.Journal of molecular biology · 2022Article
- Dynamics of protein kinases and pseudokinases by HDX-MS.Methods in enzymology · 2022Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.Bioorganic & medicinal chemistry · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.