Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Editorial
. 2023 Oct 18:12:e92753.
doi: 10.7554/eLife.92753.

Probing conformational dynamics to understand kinase inhibition

Ian R Outhwaite  1 , Markus A Seeliger  1
Affiliations
Editorial

Probing conformational dynamics to understand kinase inhibition

Ian R Outhwaite et al. Elife. .

Abstract

Why do some inhibitors select the on-state in ERK2, a kinase that is involved in many signaling pathways in cells, whereas others bind to more than one conformation?

Keywords: ERK2; MAP kinase; NMR; allosteric regulation; biochemistry; chemical biology; hydrogen-deuterium exchange mass spectrometry; inhibitor; none.

PubMed Disclaimer

Conflict of interest statement

IO, MS No competing interests declared

Figures

Figure 1.
Figure 1.. Comparing different ERK2 inhibitors.
(A) BVD523, VTX11e and 13 of the 17 ERK2 inhibitors studied by Anderson et al. select for the R-state when binding to the ERK2 kinase. GCD0994, ATG017 and 3 of the 17 inhibitors do not select for the R-state: these inhibitors have similar structures, with a bulky chemical group (red circle) on their right side. (B) A close-up view of ATG017 (red/grey/blue) bound to ERK2 (beige). With most inhibitors the Gly-loop of ERK2 can bend downwards into a highly stable closed position that is associated with the R-state. With ATG017, however, the bulky chemical group (red) prevents the Gly-loop from reaching this position, so ERK2 is free to assume more than one conformation.
See this image and copyright information in PMC

Comment on

  • doi: 10.7554/eLife.91507

References

    1. Anderson JW, Vaisar D, Jones DN, Pegram LM, Chen H, Moffat JG, Ahn NG. Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2. eLife. 2023;12:RP91507. doi: 10.7554/eLife.91507.1. - DOI - PMC - PubMed
    1. Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997;90:859–869. doi: 10.1016/s0092-8674(00)80351-7. - DOI - PubMed
    1. Flemington V, Davies EJ, Robinson D, Sandin LC, Delpuech O, Zhang P, Hanson L, Farrington P, Bell S, Falenta K, Gibbons FD, Lindsay N, Smith A, Wilson J, Roberts K, Tonge M, Hopcroft P, Willis SE, Roudier MP, Rooney C, Coker EA, Jaaks P, Garnett MJ, Fawell SE, Jones CD, Ward RA, Simpson I, Cosulich SC, Pease JE, Smith PD. AZD0364 Is a potent and selective ERK1/2 inhibitor that enhances antitumor activity in KRAS-mutant tumor models when combined with the MEK inhibitor, Selumetinib. Molecular Cancer Therapeutics. 2021;20:238–249. doi: 10.1158/1535-7163.MCT-20-0002. - DOI - PubMed
    1. Lavoie H, Gagnon J, Therrien M. ERK signalling: A master regulator of cell behaviour, life and fate. Nature Reviews Molecular Cell Biology. 2020;21:607–632. doi: 10.1038/s41580-020-0255-7. - DOI - PubMed
    1. Roskoski R. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacological Research. 2019;142:151–168. doi: 10.1016/j.phrs.2019.01.039. - DOI - PubMed

Publication types