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Exploring a new ligand binding site of G protein-coupled receptors

Abstract

Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcho-line receptors. Our results indicate that unlike the synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket. We also discovered that the most recently resolved crystal structure of LTB4 receptor comprised a bound inverse agonist, which extended its benzamidine moiety to the same binding pocket discovered in this work. Analysis on all resolve GPCR crystal structures indicated that this new pocket could exist in most receptors. Our findings provide new opportunities for GPCR drug discovery.

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Publication details

The article was received on 12 Apr 2018, accepted on 12 Jul 2018 and first published on 13 Jul 2018


Article type: Edge Article
DOI: 10.1039/C8SC01680A
Citation: Chem. Sci., 2018, Accepted Manuscript
  • Open access: Creative Commons BY-NC license
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    Exploring a new ligand binding site of G protein-coupled receptors

    H.C. S. Chan, J. Wang, K. Palczewski, S. Filipek, H. Vogel, Z. Liu and S. Yuan, Chem. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C8SC01680A

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