Recent advances in the structural biology of tyrosine kinases

Rygiel, Karolina A.; Elkins, J.M.

doi:10.1016/j.sbi.2023.102665

Cited by 5 publications

(1 citation statement)

References 60 publications

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“…Upon extracellular ligand binding, the RTKs form oligomers and activate their intracellular kinase domains, leading to the transmission of a signal into the cytoplasm. The TKs represent most targets for kinase inhibitors currently used clinically [32][33][34].…”

Section: The Tyrosine Kinases (Tks)mentioning

confidence: 99%

The Importance of Kinases in Retinal Degenerative Diseases

Santos,

Ambrósio,

Léger

2024

Kinases and Phosphatases

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Kinases play crucial roles in the pathophysiology of retinal degenerative diseases. These diseases, such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa, are characterized by progressive degeneration of retinal cells, including photoreceptors, ganglion cells, vascular cells, and retinal pigment epithelium, among others. The involvement of kinases in cell survival and apoptosis, immune responses and inflammation regulation, mitochondrial functions and mitophagy, autophagy, and proteostasis is crucial for maintaining cellular homeostasis and responding to various stressors. This review highlights the importance of studying kinases to better understand their functions and, regulation permitting, enable the identification of novel molecular players or potential drug targets and, consequently, the development of more effective and precise treatments to slow or halt the progression of retinal degenerative diseases.

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Section: The Tyrosine Kinases (Tks)mentioning

confidence: 99%

The Importance of Kinases in Retinal Degenerative Diseases

Santos,

Ambrósio,

Léger

2024

Kinases and Phosphatases

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Differential effects of the N‐terminal helix of FGF8b on the activity of a small‐molecule FGFR inhibitor in cell culture and for the extracellular domain of FGFR3c in solution

Mineev,

Hargittay,

Jin

et al. 2024

FEBS Letters

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SSR128129E (SSR) is a unique small‐molecule inhibitor of fibroblast growth factor receptors (FGFRs). SSR is a high‐affinity allosteric binder that selectively blocks one of the two major FGFR‐mediated pathways. The mechanisms of SSR activity were studied previously in much detail, allowing the identification of its binding site, located in the hydrophobic groove of the receptor D3 domain. The binding site overlaps with the position of an N‐terminal helix, an element exclusive for the FGF8b growth factor, which could potentially convert SSR from an allosteric inhibitor into an orthosteric blocker for the particular FGFR/FGF8b system. In this regard, we report here on the structural and functional investigation of FGF8b/FGFR3c system and the effects imposed on it by SSR. We show that SSR is equally or more potent in inhibiting FGF8b‐induced FGFR signaling compared to FGF2‐induced activation. On the other hand, when studied in the context of separate extracellular domains of FGFR3c in solution with NMR spectroscopy, SSR is unable to displace the N‐terminal helix of FGF8b from its binding site on FGFR3c and behaves as a weak orthosteric inhibitor. The substantial inconsistency between the results obtained with cell culture and for the individual water‐soluble subdomains of the FGFR proteins points to the important role played by the cell membrane.

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

Navarro,

Alonso,

Martínez‐Pérez

et al. 2024

Proteins

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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.

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Recent advances in the structural biology of tyrosine kinases

Cited by 5 publications

References 60 publications

The Importance of Kinases in Retinal Degenerative Diseases

The Importance of Kinases in Retinal Degenerative Diseases

Differential effects of the N‐terminal helix of FGF8b on the activity of a small‐molecule FGFR inhibitor in cell culture and for the extracellular domain of FGFR3c in solution

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

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