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COMPUTATIONAL DESIGN

Tailor-made GPCRs

Nature Chemical Biology volume 16, pages 5–6 (2020)Cite this article

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An in silico directed evolution approach using first principles of allostery predicts the effects of protein sequence and structure variation on constitutive activity and ligand response in GPCRs.

In eukaryotes, signal transduction across cell membranes in response to external input is often governed by a diverse superfamily of integral membrane proteins known as G-protein-coupled receptors (GPCRs). In humans there over 800 GPCRs, whose job is to regulate many central processes such as visual and olfactory signaling, taste, neurotransmitter response, cell homeostasis, immune response and autonomic response. Remarkably, all GPCRs share a common seven-transmembrane topology. Many of these receptors are believed to couple through multiple G proteins and arrestin proteins, resulting in a complex interactome and multiple signaling responses, whose intensities are biased by both the environment and the ligand. To explain this complexity, it has been suggested that most ligand-activated GPCRs are ‘weakly coupled’ and sample multiple conformations. As such, it is by no means obvious how binding by a given ligand enables unique allosteric pathway(s). Here, ‘allostery’ refers to long-range communication between the ligand-binding site on a GPCR and the cognate partner protein. In this issue, the work of Chen et al. brings together computational approaches that help identify the role of specific residues in stabilizing the inactive or active forms of the receptor while also predicting allosteric pathways associated with activation1. Taking this one step further, the authors make use of homology modeling and computational tools to predict the effect of mutations on stabilities of inactive or active forms of the receptor and on coupling. In this way, they are able to identify facets of the receptor that are important for biasing specific functional states while at the same time facilitating specific activation pathways. This not only helps to validate our understanding of allostery, but also—by examining huge numbers of mutations—makes it possible to design anew or repurpose existing receptors.

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Fig. 1: Repurposing GPCRs by focusing on conformational stability and allosteric networks.

References

  1. Chen, K.-Y.M., Keri, D. & Barth, P. Nat. Chem. Biol. https://doi.org/10.1038/s41589-019-0407-2 (2019).

  2. Flock, T. et al. Nature 524, 173–179 (2015).

    Article  CAS  Google Scholar 

  3. Dror, R. O. et al. Proc. Natl Acad. Sci. USA 108, 18684–18689 (2011).

    Article  CAS  Google Scholar 

  4. Lee, S., Nivedha, A. K., Tate, C. G. & Vaidehi, N. Structure 27, 703–712.e3 (2019).

    Article  CAS  Google Scholar 

  5. Johnston J. M., Filizola, M. In G Protein-Coupled Receptors - Modeling and Simulation. Advances in Experimental Medicine and Biology, vol 796 (ed Filizola, M.) 95–125 (Springer, Dordrecht, 2014).

  6. Lovera, S., Cuzzolin, A., Kelm, S., De Fabritiis, G. & Sands, Z. A. Sci. Rep. 9, 14199 (2019).

    Article  Google Scholar 

  7. Perica, T. et al. Science 346, 1254346 (2014).

    Article  Google Scholar 

  8. Vaidehi, N. & Bhattacharya, S. Curr. Opin. Pharmacol. 30, 76–83 (2016).

    Article  CAS  Google Scholar 

  9. Chen, K.-Y. M., Zhou, F., Fryszczyn, B. G. & Barth, P. Proc. Natl Acad. Sci. USA 109, 13284–13289 (2012).

    Article  CAS  Google Scholar 

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  1. Departments of Chemistry and Biochemistry, University of Toronto, Toronto, Canada

    R. Scott Prosser

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  1. R. Scott Prosser
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Correspondence to R. Scott Prosser.

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Prosser, R.S. Tailor-made GPCRs. Nat Chem Biol 16, 5–6 (2020). https://doi.org/10.1038/s41589-019-0427-y

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