Structural basis for allosteric regulation of GPCRs by sodium ions. Science 2012 Jul 13;337(6091):232-6
Date
07/17/2012Pubmed ID
22798613Pubmed Central ID
PMC3399762DOI
10.1126/science.1219218Scopus ID
2-s2.0-84861961427 (requires institutional sign-in at Scopus site) 758 CitationsAbstract
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.
Author List
Liu W, Chun E, Thompson AA, Chubukov P, Xu F, Katritch V, Han GW, Roth CB, Heitman LH, IJzerman AP, Cherezov V, Stevens RCAuthor
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine A2 Receptor AgonistsAdenosine A2 Receptor Antagonists
Allosteric Regulation
Cholesterol
Crystallography, X-Ray
Cytochrome b Group
Escherichia coli Proteins
HEK293 Cells
Humans
Hydrogen Bonding
Ligands
Lipid Bilayers
Lipids
Models, Molecular
Protein Conformation
Protein Engineering
Protein Structure, Secondary
Receptor, Adenosine A2A
Recombinant Fusion Proteins
Sodium
Triazines
Triazoles
Water
