Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions
Year: 2012
Type: article
Abstract: 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 A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL 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 Asp(2.50). 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.
Source: Science
Institution: Scripps Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G2363639003, G402281873, JCIMPT-Complexes, Why do drugs fail in man? Drug-target residence time as a novel parameter in drug design and discovery, and the development of novel biochemical screening methods for that parameter., GPCR Network, Molecular Mechanism of Allosteric Modulation of the Oxytocin Receptor by Sterols, The crystal structure of the adenosine A2A receptor: the follow up
OpenAlex ID: W2039399096