Unknown

Dataset Information

0

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


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.

SUBMITTER: White KL 

PROVIDER: S-EPMC5810373 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

White Kate L KL   Eddy Matthew T MT   Gao Zhan-Guo ZG   Han Gye Won GW   Lian Tiffany T   Deary Alexander A   Patel Nilkanth N   Jacobson Kenneth A KA   Katritch Vsevolod V   Stevens Raymond C RC  

Structure (London, England : 1993) 20180127 2


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 A<sub>2A</sub> adenosine receptor, D52<sup>2.50</sup>N and S91<sup>3.39</sup>A. Both structures present an overall active-like conformation; however, the variants show key changes i  ...[more]

Similar Datasets

| S-EPMC4106411 | biostudies-literature
| S-EPMC2817978 | biostudies-literature
| S-EPMC8529114 | biostudies-literature
| S-EPMC7864071 | biostudies-literature
| S-EPMC5751122 | biostudies-literature
| S-EPMC7236428 | biostudies-literature
| S-EPMC3399762 | biostudies-literature
| S-EPMC11362167 | biostudies-literature
| S-EPMC9652377 | biostudies-literature
| S-EPMC3307325 | biostudies-literature