ArticleProceedings of the National Academy of Sciences of the United States of America2014
Phosphorylation releases constraints to domain motion in ERK2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 77 citations in OpenAlex.
- Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling That Promotes Cell State Transition and Confers Therapeutic Vulnerabilities.Cancer research · 2026Article
- Exploring the interplay between protein conformational changes and phosphorylation in a pancreatic cancer cell and stellate cell coculture system.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A Fast Method to Monitor Tyrosine Kinase Inhibitor Mechanisms.Journal of medicinal chemistry · 2024Article
- Exploring the conformational landscapes of protein kinases: perspectives from FRET and DEER.Biochemical Society transactions · 2024Review
- 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
- Navigating the ERK1/2 MAPK Cascade.Biomolecules · 2023Review
- Mutation in the Common Docking Domain Affects MAP Kinase ERK2 Catalysis and Stability.Cancers · 2023Article
- Article
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- Retrospective study for the universal applicability of the residue-based linear free energy relationship in the two-state exchange of protein molecules.Scientific reports · 2022Article
- ERK1/2-RSK2 Signaling in Regulation of ERα-Mediated Responses.Endocrinology · 2022Review
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers.Nature communications · 2022Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Conformational states dynamically populated by a kinase determine its function.Science (New York, N.Y.) · 2020Article
- Activation Loop Dynamics Are Coupled to Core Motions in Extracellular Signal-Regulated Kinase-2.Biochemistry · 2020Article
- Spotlight on the Ballet of Proteins: The Structural Dynamic Properties of Proteins Illuminated by Solution NMR.International journal of molecular sciences · 2020Review
- Kinase Activation by Small Conformational Changes.Journal of chemical information and modeling · 2020Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Protein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR (13)C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methyl side chains on Ile, Leu, and Val residues showed changes in conformational exchange dynamics in the microsecond-to-millisecond time regime between the different activity states of ERK2. In inactive, unphosphorylated ERK2, localized conformational exchange was observed among methyl side chains, with little evidence for coupling between residues. Upon dual phosphorylation by MAP kinase kinase 1, the dynamics of assigned methyls in ERK2 were altered throughout the conserved kinase core, including many residues in the catalytic pocket. The majority of residues in active ERK2 fit to a single conformational exchange process, with kex ≈ 300 s(-1) (kAB ≈ 240 s(-1)/kBA ≈ 60 s(-1)) and pA/pB ≈ 20%/80%, suggesting global domain motions involving interconversion between two states. A mutant of ERK2, engineered to enhance conformational mobility at the hinge region linking the N- and C-terminal domains, also induced two-state conformational exchange throughout the kinase core, with exchange properties of kex ≈ 500 s(-1) (kAB ≈ 15 s(-1)/kBA ≈ 485 s(-1)) and pA/pB ≈ 97%/3%. Thus, phosphorylation and activation of ERK2 lead to a dramatic shift in conformational exchange dynamics, likely through release of constraints at the hinge.
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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.