PXD048311 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | HDX-MS Analysis of Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2 |
Description | 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, 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 P+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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-03-20 |
AnnouncementXML | Submission_2024-03-20_08:51:47.994.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Jake Anderson |
SpeciesList | scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; |
ModificationList | phosphorylated residue |
Instrument | Synapt MS |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-01-08 07:38:56 | ID requested | |
⏵ 1 | 2024-03-20 08:51:48 | announced | |
Publication List
Keyword List
submitter keyword: ATP-competitive inhibition, MAP kinase,HDX-MS, conformation selection, ERK2 |
Contact List
Natalie G. Ahn |
contact affiliation | University of Colorado Boulder |
contact email | natali.ahn@colorado.edu |
lab head | |
Jake Anderson |
contact affiliation | University of Colorado Boulder |
contact email | jake.anderson@colorado.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD048311
- Label: PRIDE project
- Name: HDX-MS Analysis of Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2