Interrogating Regulatory Mechanisms in Signaling Proteins by Allosteric Inhibitors and Activators: A Dynamic View Through the Lens of Residue Interaction Networks

  • Lindy Astl
  • Amanda Tse
  • Gennady M. VerkhivkerEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)


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.


Allosteric regulation Siganling proteins Allosteric modulators Conformational dynamics NMR Spectroscopy Residue coevolution Residue interaction networks Protein kinases Drug discovery 


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Lindy Astl
    • 1
  • Amanda Tse
    • 1
  • Gennady M. Verkhivker
    • 1
    • 2
    • 3
    Email author
  1. 1.Graduate Program in Computational and Data Sciences, Schmid College of Science and TechnologyChapman UniversityOrangeUSA
  2. 2.Department of Biomedical and Pharmaceutical SciencesChapman University School of PharmacyIrvineUSA
  3. 3.Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California San DiegoLa JollaUSA

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