Tracking mutation and drug-driven alterations of oncokinase conformations

Feichtner, Andreas; Kugler, Valentina; Schwaighofer, Selina; Nuener, Thomas; Fleischmann, Jakob; Stefan, Eduard

doi:10.1007/s12254-021-00790-6

“…On the cellular level, kinases act as molecular switches, adopting conformational states that align with an active (ON) or inactive (OFF) kinase state ( Huse and Kuriyan (2002) , Yamaguchi and Hendrickson (1996) , Lopez et al (2019) , Feichtner et al (2022) ). These ON and OFF states of protein kinases signify a switch-like behavior which is governed by a collection of molecular mechanisms (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted January 18, 2024. ; https://doi.org/10.1101/2024.01.11.575270 doi: bioRxiv preprint align with an active (ON) or inactive (OFF) kinase state (Huse and Kuriyan (2002), Yamaguchi and Hendrickson (1996), Lopez et al ( ), Feichtner et al (2022). These ON and OFF states of protein kinases signify a switch-like behavior which is governed by a collection of molecular mechanisms (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Kugler,

Schwaighofer,

Feichtner

et al. 2024

Preprint

Self Cite

0

View full text Add to dashboard Cite

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the Kinase Conformation (KinCon)-reporter system. We first tracked BRAF-kinase activity conformation changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1-kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP-kinases in response to TNF-pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps identify cellular factors that impact drug efficacies. The understanding of the dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

show abstract

“…On the cellular level, kinases act as molecular switches, adopting conformational states that align with an active (ON) or inactive (OFF) kinase state ( Huse and Kuriyan, 2002 , Yamaguchi and Hendrickson, 1996 , Lopez et al, 2020 , Feichtner et al, 2022 ). These ON and OFF states of protein kinases signify a switch-like behavior which is governed by a collection of molecular mechanisms ( Figure 1A ).…”

Section: Introductionmentioning

confidence: 99%

Impact of protein and small molecule interactions on kinase conformations

Kugler,

Schwaighofer,

Feichtner

et al. 2024

eLife

Self Cite

0

View full text Add to dashboard Cite

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the Kinase Conformation (KinCon)-reporter system. We first tracked BRAF-kinase activity conformation changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1-kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP-kinases in response to TNF-pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps identify cellular factors that impact drug efficacies. The understanding of the dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

show abstract

Unveiling the Complexity of cis‐Regulation Mechanisms in Kinases: A Comprehensive Analysis

Navarro,

Alonso,

Martínez‐Pérez

et al. 2024

Proteins

0

View full text Add to dashboard Cite

Protein cis‐regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis. To accomplish this, we curated an extensive dataset of kinases featuring annotated CREs, organized into homolog families through multiple sequence alignments. Key molecular attributes, including disorder and secondary structure content, active and ATP‐binding sites, post‐translational modifications, and disease‐associated mutations, were systematically mapped onto all sequences. Additionally, we explored the potential for conformational changes between active and inactive states. Finally, we explored the presence of these kinases within membraneless organelles and elucidated their functional roles therein. CREs display a continuum of structures, ranging from short disordered stretches to fully folded domains. The adaptability demonstrated by CREs in achieving the common goal of kinase inhibition spans from direct autoinhibitory interaction with the active site within the kinase domain, to CREs binding to an alternative site, inducing allosteric regulation revealing distinct types of inhibitory mechanisms, which we exemplify by archetypical representative systems. While this study provides a systematic approach to comprehend kinase CREs, further experimental investigations are imperative to unravel the complexity within distinct kinase families. The insights gleaned from this research lay the foundation for future studies aiming to decipher the molecular basis of kinase dysregulation, and explore potential therapeutic interventions.

show abstract

Tracking mutation and drug-driven alterations of oncokinase conformations

Cited by 7 publications

References 45 publications

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Impact of protein and small molecule interactions on kinase conformations

Unveiling the Complexity of cis‐Regulation Mechanisms in Kinases: A Comprehensive Analysis

Contact Info

Product

Resources

About