NMR Spectroscopic Investigations of the Activated p38α Mitogen‐Activated Protein Kinase
Abstract
Phosphorylation of protein kinases is a central mechanism involved in numerous cellular regulatory circuits, both in prokaryotic and eukaryotic cells. An understanding of the structural and functional consequences of protein phosphorylation is of considerable importance for the design of selective, small‐molecule kinase inhibitors. NMR spectroscopy is a central method to support structure‐based drug design. Here, we present the NMR assignment of the activated p38α kinase and compare it to the NMR assignment of unphosphorylated p38α. Conformational changes in solution induced by activation can be located to the activation loop, an adjacent loop, and an insert part of the polypeptide chain that is specific for the family of mitogen‐activated kinases. Deuterium‐exchange experiments additionally revealed differences in exchange behavior for two residues in an alanine‐rich helix–loop motif that becomes more flexible upon binding of an ATP analogue and a substrate peptide.
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Sequence-specific backbone assignment has been achieved for p38a (82%), activated pTpYp38a (56%), and ERK2 (65%), including key MAPK regulatory elements.
“The basis of any NMR spectroscopy analysis is the sequence-specific backbone assignment, which has been achieved for p38a 47,58,61 (82%), activated pTpYp38a 69 (56%) and ERK2 65 (65%) and include key MAPK regulatory elements, especially the KIM binding pockets (93%/95% for p38a/ERK2) the glycine-rich loops (100%/100% for p38a/ERK2) and the activation loops (83%/none for p38a/ERK2).”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [69]
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Molecular basis of MAP kinase regulation
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- Authors
- Nielsen, G., & Schwalbe, H.
- Affiliations
- Goethe University Frankfurt (DE)
- Corresponding author
- Schwalbe, Harald
- ORCID
- Schwalbe, Harald
- Venue
- ChemBioChem
- Publisher
- Wiley
- Published
- 2011-10-19
- Volume
- 12
- Issue
- 17
- Pages
- 2599-2607
- ISSN
- 1439-4227 (ISSN-L)
- 1439-7633
- OpenAlex
- W2085267380
- Cited by
- 15
- References
- 34
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 2 · 2018: 1 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ChemBioChem (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- p38α MAPK, mitogen-activated protein kinase, kinase activation, protein phosphorylation, NMR resonance assignment, activation loop, conformational change, hydrogen-deuterium exchange, structure-based drug design, kinase inhibitors
- MeSH terms
- Adenosine Triphosphate, Enzyme Activation, Magnetic Resonance Spectroscopy, Peptides, Phosphorylation, Protein Binding, Recombinant Proteins, Deuterium Exchange Measurement, Mitogen-Activated Protein Kinase 14
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