Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

By Wei Liu, E. Chun, A. Thompson, P. Chubukov, Fei Xu, Vsevolod Katritch, G. Han, Christopher B. Roth, L. Heitman, Adriaan P. IJzerman and 2 more. Science, 2012

927 citations recorded by the source corpus.

GPCR Close-Up Structures of G protein–coupled receptors (GPCRs) determined in the past few years, have provided insight into the function of this important family of membrane proteins. Liu et al. (p. 232) used a protein-engineering strategy to produce a stabilized version of the human A2Aadenosine receptor (A2AAR). The high-resolution structure reveals the position of about 60 internal waters, which suggests an almost continuous channel in the GPCR and can explain the allosteric effects of Na+ on ligand binding and how cholesterol may contribute to GPCR stabilization. A protein-engineering strategy yields a closer look at the receptor-bound water, sodium, and lipid molecules. Pharmacological responses of G protein–coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A2A adenosine receptor by replacing its third intracellular loop with apocytochrome b562RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp2.50. Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/662fb09a1750dd888a223624e5b5053513a1c035

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Citations in the corpus

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor*♦ (2015, background): “The sodium site was previously discovered in high resolution structures of A2A-adenosine (36) and -opioid receptors ( -”
Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV (2017, background): “Visible water molecules also continued from the receptor-binding pocket into the TM domain where they appeared to play a role in stabilizing the inactive conformation (Figure 4), similar to the inactive state structures of the adenosine A2A and d-opioid receptors (Fenalti et al., 2014; Liu et al., 2”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “39 residues and structured water, rationalizing the stabilizing effect of the Na+ ion on the inactive receptor state (57).”
Enhancing structure prediction and design of soluble and membrane proteins with explicit solvent-protein interactions (2017, methodology): “…hybrid solvent homology modeling technique recapitulated native protein local conformations and interacting water networks critically involved in ligand binding or membrane receptor signaling (Gutiérrez-de-Terán et al., 2013; Liu et al., 2012; Nygaard et al., 2010; Valentin-Hansen et al., 2015).”
Harnessing the power of an X-ray laser for serial crystallography of membrane proteins crystallized in lipidic cubic phase (2020, methodology): “We compare this model with the 1.8 Å synchrotron structure [PDB entry 4eiy (Liu et al., 2012)] as well as with other published A2AAR structures from XFEL SFX [PDB entries 5nm4 (Weinert et al., 2017) and 5k2d (Batyuk et al., 2016)] and synchrotron SMX experiments [PDB entry 5nlx (Weinert et al.,…”