Interrogating Regulatory Mechanisms in Signaling Proteins by Allosteric Inhibitors and Activators: A Dynamic View Through the Lens of Residue Interaction Networks
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Description
Computational studies of allosteric interactions have witnessed a recent renaissance fueled by the growing interest in modeling of the complex molecular assemblies and biological networks. Allosteric interactions in protein structures allow for molecular communication in signal transduction networks. In this chapter, we discuss recent developments in understanding of allosteric mechanisms and interactions of protein systems, particularly in the context of structural, functional, and computational studies of allosteric inhibitors and activators. Computational and experimental approaches and advances in understanding allosteric regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress in the development of allosteric modulators and highlight most challenging questions in the field. The abundance and diversity of genetic, structural, and biochemical data underlies the complexity of mechanisms by which targeted and personalized drugs can combat mutational profiles in protein kinases. Structural and computational studies of protein kinases have generated in recent decade significant insights that allowed leveraging knowledge about conformational diversity and allosteric regulation of protein kinases in the design and discovery of novel kinase drugs. We discuss recent developments in understanding multilayered allosteric regulatory machinery of protein kinases and provide a systematic view of the current state in understanding molecular basis of allostery mediated by kinase inhibitors and activators. In conclusion, we highlight the current status and future prospects of computational biology approaches in bridging the basic science of protein kinases with the discovery of anticancer therapies.
ISBN
978-981-13-8719-7
Publication Date
11-10-2019
Publisher
Springer Nature Singapore Pte Ltd.
City
Singapore
Keywords
allosteric regulation, signaling proteins, allosteric modulators, conformational dynamics, NMR spectroscopy, residue coevolution, residue interaction networks, protein kinases, drug discovery
Disciplines
Amino Acids, Peptides, and Proteins | Cancer Biology | Enzymes and Coenzymes | Oncology | Other Chemicals and Drugs | Other Computer Sciences | Other Medicine and Health Sciences
Recommended Citation
Astl L., Tse A., Verkhivker G.M. (2019) Interrogating Regulatory Mechanisms in Signaling Proteins by Allosteric Inhibitors and Activators: A Dynamic View Through the Lens of Residue Interaction Networks. In: Zhang J., Nussinov R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore
Copyright
Springer
Comments
In Jian Zhang and Ruth Nussinov (Eds.), Protein Allostery in Drug Discovery.
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