Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2
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 b...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2024-03-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/91507 |
| _version_ | 1797238866659246080 |
|---|---|
| author | Jake W Anderson David Vaisar David N Jones Laurel M Pegram Guy P Vigers Huifen Chen John G Moffat Natalie G Ahn |
| author_facet | Jake W Anderson David Vaisar David N Jones Laurel M Pegram Guy P Vigers Huifen Chen John G Moffat Natalie G Ahn |
| author_sort | Jake W Anderson |
| collection | DOAJ |
| 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 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 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. |
| first_indexed | 2024-04-24T17:42:27Z |
| format | Article |
| id | doaj.art-089ca721611842539172a5e7837a22f2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T17:42:27Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-089ca721611842539172a5e7837a22f22024-03-27T19:36:15ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011210.7554/eLife.91507Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2Jake W Anderson0https://orcid.org/0000-0001-8757-7408David Vaisar1David N Jones2Laurel M Pegram3Guy P Vigers4Huifen Chen5John G Moffat6Natalie G Ahn7https://orcid.org/0000-0002-2690-2630Department of Biochemistry, University of Colorado, Boulder, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesDepartment of Pharmacology, University of Colorado Anschutz Medical Center, Boulder, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesArrayBioPharma, Inc., Boulder, United StatesGenentech, Inc., South San Francisco, United StatesGenentech, Inc., South San Francisco, United StatesDepartment of Biochemistry, University of Colorado, Boulder, United StatesActivation 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 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.https://elifesciences.org/articles/91507MAP kinaseinhibitorconformation selectionNMRhydrogen exchangecancer therapeutics |
| spellingShingle | Jake W Anderson David Vaisar David N Jones Laurel M Pegram Guy P Vigers Huifen Chen John G Moffat Natalie G Ahn Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 eLife MAP kinase inhibitor conformation selection NMR hydrogen exchange cancer therapeutics |
| title | Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 |
| title_full | Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 |
| title_fullStr | Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 |
| title_full_unstemmed | Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 |
| title_short | Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 |
| title_sort | conformation selection by atp competitive inhibitors and allosteric communication in erk2 |
| topic | MAP kinase inhibitor conformation selection NMR hydrogen exchange cancer therapeutics |
| url | https://elifesciences.org/articles/91507 |
| work_keys_str_mv | AT jakewanderson conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT davidvaisar conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT davidnjones conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT laurelmpegram conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT guypvigers conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT huifenchen conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT johngmoffat conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 AT nataliegahn conformationselectionbyatpcompetitiveinhibitorsandallostericcommunicationinerk2 |