Special Issue: MAPK Signaling Cascades in Human Health and Diseases DOI Open Access
Rony Seger

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 11226 - 11226

Опубликована: Окт. 18, 2024

In order to survive and fulfil their functions, cells of any organism need be able respond a large number extracellular factors, also termed stimuli [...]

Язык: Английский

Navigating the ERK1/2 MAPK Cascade DOI Creative Commons
Ana Martín-Vega, Melanie H. Cobb

Biomolecules, Год журнала: 2023, Номер 13(10), С. 1555 - 1555

Опубликована: Окт. 20, 2023

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all types. Notably, ERK1/2 are implicated in specific context-dependent manner as stem cells pancreatic β-cells. Alterations the different components of this result dysregulation effector kinases which communicate with hundreds substrates. Aberrant activation contributes to range disorders, cancer. This review provides an overview structure, activation, regulation, mutational frequency tiers cascade; particular focus on ERK1/2. We highlight importance scaffold proteins that contribute kinase localization coordinate interaction dynamics substrates, activators, inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues field.

Язык: Английский

Процитировано

47

Allo-targeting of the kinase domain: Insights from in silico studies and comparison with experiments DOI
Ji Young Lee, Emma Gebauer, Markus A. Seeliger

и другие.

Current Opinion in Structural Biology, Год журнала: 2024, Номер 84, С. 102770 - 102770

Опубликована: Янв. 11, 2024

Язык: Английский

Процитировано

3

ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events DOI Creative Commons
Clil Regev, Hyunbum Jang, Ruth Nussinov

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 2, 2025

Abstract ERK, a coveted proliferation drug target, is pivotal kinase in the Ras/ERK signaling cascade. Despite this, crucial questions about its activation have not been fully explored on foundational, conformational level. Such include (i) Why ERK’s demands dual phosphorylation ; (ii) What role of each site loop and (iii) Exactly how (ordered) steps affect ensembles , their propensities restriction to narrower range favoring catalytic action . Here we used explicit molecular dynamics simulations study stability changes different stages along process. The initial monophosphorylation event elongates enable successive phosphorylations, which reintroduce stability/compactness through newly formed salt bridges. interactions by are site-dependent, with threonine’s presenting stronger electrostatic compared tyrosine’s. Dual phosphorylated ERKs revealed compact structure allows HRD motif stabilize ATP. We further observe that hinge homodimerization binding responded tri-state code based solely degree (unphosphorylated, monophosphorylated, phosphorylated) loop, confirming can allosterically influence distant regions. Last, our findings indicate threonine as second step necessary for ERK become effectively activated depends order. Collectively, offer allosteric explain why order crucial.

Язык: Английский

Процитировано

0

ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events DOI
Clil Regev, Hyunbum Jang, Ruth Nussinov

и другие.

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169130 - 169130

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0

Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 DOI Creative Commons
Jake W. Anderson,

David Vaisar,

David N. M. Jones

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Сен. 28, 2023

Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described a global between two conformational states active kinase, named ‘L’ ‘R,’ where R is associated with catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, properties conformation selection for R-state, revealing movements activation loop that are allosterically coupled kinase site. However, features inhibitors important R-state unknown. Here, we survey panel ERK using HDX-MS identify 14 new molecules selection. They reveal effects propagated distal regions P +1 helix αF segments surrounding loop, well αL16. Crystal structures inhibitor complexes ERK2 systematic shifts Gly αC, mediated Tyr-Tyr ring stacking interaction conserved Lys-Glu salt bridge. The findings suggest model involving small N-lobe promote compactness within site alter mobility loop. Such might exploited modulate docking interface used substrates effectors.

Язык: Английский

Процитировано

7

Probing conformational dynamics to understand kinase inhibition DOI Creative Commons
Ian R Outhwaite, Markus A. Seeliger

eLife, Год журнала: 2023, Номер 12

Опубликована: Окт. 18, 2023

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

Язык: Английский

Процитировано

4

Special Issue: MAPK Signaling Cascades in Human Health and Diseases DOI Open Access
Rony Seger

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 11226 - 11226

Опубликована: Окт. 18, 2024

In order to survive and fulfil their functions, cells of any organism need be able respond a large number extracellular factors, also termed stimuli [...]

Язык: Английский

Процитировано

0