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Is there a common allosteric binding site for G-protein coupled receptors?

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Abstract

Targeting the allosteric sites on G-protein coupled receptors (GPCRs) for drug discovery is attracting increased interest. Given a GPCR target, identifying the allosteric binding sites in it remains a challenge. Previous works from our and other labs suggest the intracellular region below the middle of the transmembrane (TM) domain that spatially overlaps with the G-protein binding site could contain a common allosteric site for all GPCRs. We performed several bioinformatics analyses on this site for more than 100 representative human GPCR structures. Results of the studies confirmed that the proposed region contains an allosteric site that is druggable for 89% of the GPCRs and is not 100% identical between a GPCR and its most similar homolog for 94% of the GPCRs. The physico-chemical properties and amino acid composition of this site vary among and within GPCR classes. Since this proposed region occupies the space existing in all GPCRs of known structure, it could represent a common host of an allosteric site for all GPCRs that can be targeted for structure-based allosteric drug design.

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All the data generated in this work is freely available in the supplementary materials or by contacting the corresponding author.

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Acknowledgements

The authors thank Dr. Michael Bruist at University of the Sciences in Philadelphia for proofreading the manuscript and helpful comments. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number [R15GM140406]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, 19104, USA

    Faisal Malik & Zhijun Li

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  1. Faisal Malik
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Correspondence to Zhijun Li.

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Malik, F., Li, Z. Is there a common allosteric binding site for G-protein coupled receptors?. J Comput Aided Mol Des 36, 405–413 (2022). https://doi.org/10.1007/s10822-022-00454-5

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