2. Academic Validation
  3. Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling

Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling

  • Structure. 2018 Feb 6;26(2):259-269.e5. doi: 10.1016/j.str.2017.12.013.
Kate L White 1,  Matthew T Eddy 1,  Zhan-Guo Gao 2,  Gye Won Han 1,  Tiffany Lian 1,  Alexander Deary 1,  Nilkanth Patel 1,  Kenneth A Jacobson 2,  Vsevolod Katritch 1,  Raymond C Stevens 3
Affiliations

Affiliations

  • 1 Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center, University of Southern California, 1002 West Childs Way, Los Angeles, CA 90089, USA.
  • 2 Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center, University of Southern California, 1002 West Childs Way, Los Angeles, CA 90089, USA. Electronic address: [email protected].
PMID: 29395784 DOI: 10.1016/j.str.2017.12.013
Abstract

Sodium ions are endogenous allosteric modulators of many G-protein-coupled receptors (GPCRs). Mutation of key residues in the sodium binding motif causes a striking effect on G-protein signaling. We report the crystal structures of agonist complexes for two variants in the first sodium coordination shell of the human A2A Adenosine Receptor, D522.50N and S913.39A. Both structures present an overall active-like conformation; however, the variants show key changes in the activation motif NPxxY. Changes in the hydrogen bonding network in this microswitch suggest a possible mechanism for modified G-protein signaling and enhanced thermal stability. These structures, signaling data, and thermal stability analysis with a panel of pharmacological ligands provide a basis for understanding the role of the sodium-coordinating residues on stability and G-protein signaling. Utilizing the D2.50N variant is a promising method for stabilizing class A GPCRs to accelerate structural efforts and drug discovery.

Keywords

GPCR; adenosine receptor; allosteric modulators; cell signaling; crystallography; sodium binding; structural biology.

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