Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2 DOI Open Access
Jake W. Anderson,

David Vaisar,

David N. M. Jones

и другие.

Опубликована: Янв. 3, 2024

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

Therapeutic advances of targeting receptor tyrosine kinases in cancer DOI Creative Commons
Ciprian Tomuleasa, Adrian Bogdan Țigu, Raluca Munteanu

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 14, 2024

Abstract Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression certain RTKs, are critical creating environments conducive tumor development. Following discovery, extensive research has revealed how RTK dysregulation contributes oncogenesis, with many subtypes showing dependency on aberrant signaling for proliferation, survival progression. These findings paved the way targeted therapies that aim inhibit crucial biological pathways cancer. As result, RTKs emerged as primary targets anticancer therapeutic Over past two decades, this led synthesis validation numerous small molecule kinase inhibitors (TKIs), now effectively utilized treating various types. In manuscript we provide comprehensive understanding context We explored alterations specific receptors across different malignancies, special dedicated examination current inhibitors, highlighting potential therapies. By integrating latest evidence, seek elucidate pivotal biology efficacy inhibition promising treatment outcomes.

Язык: Английский

Процитировано

29
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: 2024, Номер 12

Опубликована: Март 27, 2024

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
Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases DOI

Lena Grogan,

Paul Shapiro

Advances in pharmacology, Год журнала: 2024, Номер unknown, С. 181 - 207

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

5
The RAS-Regulated RAF-MEK1/2-ERK1/2 Protein Kinase Pathway: The Path Most Traveled in RASopathies DOI
Rafał Dutkiewicz, Hayley J. Sharpe, Simon J. Cook

и другие.

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

4
Assessing the predicted impact of single amino acid substitutions in MAPK proteins for CAGI6 challenges DOI
Paola Turina, Maria Petrosino,

Carlos A. Enriquez Sandoval

и другие.

Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 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
The complex impact of cancer-related missense mutations on the stability and on the biophysical and biochemical properties of MAPK1 and MAPK3 somatic variants DOI Creative Commons
Maria Petrosino,

Leonore Novak,

Alessandra Pasquo

и другие.

Human Genomics, Год журнала: 2023, Номер 17(1)

Опубликована: Окт. 27, 2023

Abstract Mitogen-activated protein kinases 1 and 3 (MAPK1 MAPK3), also called extracellular regulated (ERK2 ERK1), are serine/threonine kinase activated downstream by the Ras/Raf/MEK/ERK signal transduction cascade that regulates a variety of cellular processes. A dysregulation MAPK is frequently associated to missense mutations on its components may be related many pathologies, including cancer. In this study we selected from COSMIC database set MAPK1 MAPK3 somatic variants found in cancer tissues carrying distributed all over sequences. The proteins were expressed as pure recombinant proteins, their biochemical biophysical properties have been studied comparison with wild type. lead changes tertiary arrangements variants. thermodynamic stability type has investigated non-phosphorylated phosphorylated form. Significant differences thermal stabilities most observed, well catalytic efficiencies. energetics reaction affected for both proteins. variation enzyme catalysis observed MAPK1/3 suggest local change residue, distant site, long-distance effects reflect globally functions.

Язык: Английский

Процитировано

5
RAF inhibitors activate the integrated stress response by direct activation of GCN2 DOI Creative Commons
Rebecca Gilley, Andrew M. Kidger,

Graham W. Neill

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 16, 2024

Abstract Paradoxical RAF activation by chemical inhibitors (RAFi) is a well-understood ‘on-target’ biological and clinical response. In this study, we show that range of RAFi drive ERK1/2-independent the Unfolded Protein Response (UPR), including expression ATF4 CHOP, required translation initiation factor eIF2α. RAFi-induced CHOP was not reversed inhibition PERK, known upstream activator eIF2α-dependent Integrated Stress (ISR). Rather, found exposure activated GCN2, an alternate eIF2α kinase, leading to (and ERK1/2-independent) expression. The GCN2 kinase inhibitor A-92, RNAi, knock-out or ISRIB (an antagonist) all indicating require activate ISR. also full-length recombinant in vitro cells, generating characteristic ‘bell-shaped’ concentration-response curve, reminiscent RAFi-driven paradoxical WT dimers. Activation ISR abolished dead mutations M802A M802G gatekeeper mutations, suggesting bind directly domain; supported mechanistic structural models interaction with GCN2. Since critical pathway for determining cell survival death, our observations may be relevant use RAFi, where previously unappreciated off-target effect modulate tumour responses.

Язык: Английский

Процитировано

1
Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer DOI Creative Commons
Ana Rita Brás, Ana Rita Lopes, Nuno Mendes

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 13, 2023

Abstract KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a ruthenium compound, PMC79, that inhibits specifically mutated and downstream signaling ERK AKT proteins both “in vitro” vivo”. We demonstrated PMC79 kinase activity is selective not affecting wild-type protein. inhibition dependent on actin polymerization or proteasome. Molecular docking analysis suggests this effect might result from protein dynamics associated with mutations. low doses potentiate 5-fluorouracil anticancer effect. “In vivo” “proof concept” showed it reduces tumor growth in CAM-xenograft model induces necrosis xenograft mice model. promising “magic bullet” CRCs harboring KRAS.

Язык: Английский

Процитировано

1
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.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 12, 2023

ABSTRACT 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

1