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      Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor.

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          Abstract

          Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator. The proposed "trigger switch" for the mGlu2 involves the side chains of F6433.36a.40c, N7355.47a.47c, and W7736.48a.50c, whereas the "transmission switch" involves the Y6473.40a.44c, L7385.50a.50c, and T7696.44a.46c amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs.

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          Author and article information

          Journal
          Structure
          Structure (London, England : 1993)
          Elsevier BV
          1878-4186
          0969-2126
          Jul 05 2017
          : 25
          : 7
          Affiliations
          [1 ] Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain; Computational Chemistry, Janssen Research and Development, Calle Jarama 75A, 45007 Toledo, Spain.
          [2 ] Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium; Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA Leiden, the Netherlands.
          [3 ] Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain.
          [4 ] Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
          [5 ] Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain. Electronic address: leonardo.pardo@uab.es.
          [6 ] Computational Chemistry, Janssen Research and Development, Calle Jarama 75A, 45007 Toledo, Spain; Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: gtresade@its.jnj.com.
          Article
          S0969-2126(17)30155-7
          10.1016/j.str.2017.05.021
          28648611
          bb634a49-17a6-4e17-92cb-e22db5aaa828
          History

          mGlu,PAM,activation,allosteric modulator,class C,mGluR,molecular dynamics,transmission switch,GPCR,NAM

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