Mapping of Allosteric Druggable Sites in Activation-Associated Conformers of the M2 Muscarinic Receptor

Authors

  • Yinglong Miao,

    Corresponding author
    1. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, USA
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  • Sara E. Nichols,

    1. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA
    2. Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA
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  • J. Andrew McCammon

    1. Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA, USA
    2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA
    3. Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA
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Abstract

G-protein-coupled receptors (GPCRs) are key cellular signaling proteins and have been targeted by approximately 30–40% of marketed drugs for treating many human diseases including cancer and heart failure. Recently, we directly observed activation of the M2 muscarinic receptor through long-timescale accelerated molecular dynamics (aMD) simulation, which revealed distinct inactive, intermediate and active conformers of the receptor. Here, FTMAP is applied to search for ‘hot spots’ in these activation-associated conformers using a library of 16 organic probe molecules that represent fragments of potential drugs. Seven allosteric (non-orthosteric) binding sites are identified in the M2 receptor through the FTMAP analysis. These sites are distributed in the solvent-exposed extracellular and intracellular mouth regions, as well as the lipid-exposed pockets formed by the transmembrane α helices TM3-TM4, TM5-TM6 and TM7-TM1/TM2. They serve as promising target sites for designing novel allosteric modulators as receptor-selective drugs.

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