Their study suggests that certain agonists can stabilize these receptors, unlike what was previously believed.!--h2>
Scientists from The Scripps Research Institute have determined a new structure from G protein-coupled receptors (GPCRs). Based on their study of the structure of an agonist bound to the A2A adenosine receptor, they say that certain beliefs about agonist binding may be wrong.
The study, published on March 10 in Science Express, is titled “Structure of an Agonist-bound Human A2A Adenosine Receptor.”
Up until now, researchers had primarily been able to obtain the structures of GPCRs bound to antagonists—i.e., in their inactive but more stable forms. Some thought a receptor bound to an agonist would be too dynamic without stabilizing mutations or G-proteins bound for the receptor to be amenable to forming crystals.
The Scripps team believes that their findings prove these assumptions wrong. They obtained the structure of the human A2A adenosine receptor bound to a full agonist. The A2A adenosine receptor is a member of the GPCR family sometimes referred to as the caffeine receptor.
The team discovered that when the receptor bound to this particular agonist, it took on a new shape, as expected, but it then remained in that new conformation rather than continuing to move. “We were surprised to discover a super stabilizing agonist,” remarks Raymond C. Stevens, Ph.D., professor at the departments of molecular biology and chemistry.
“While dynamics is certainly a critical component of receptor signaling, it is not as extreme or the complete story as previously thought. The agonist we solved with the A2A structure highlights the fact that certain agonists can stabilize the receptor in a single conformation without the presence of an intracellular binding partner such as a G-protein.
“This is also teaching us that what we learn from one receptor or one agonist/antagonist interaction should not necessarily be a rule for all GPCRs at this early stage of GPCR structure discovery. We need to study multiple systems in-depth before we will really understand this receptor family.”
Like all proteins, GPCRs consist of long chains of amino acids that assemble themselves in 3-D shapes. GPCRs consist of seven helices that span the membrane of a cell. Loops connecting the helices sit both outside the cell membrane and inside the cell.
In the new study, Dr. Stevens group found that when the agonist bound the A2A receptor, helices 5, 6, and 7 underwent a dramatic shift in their positions. In contrast, helices 1 to 4 tended to stay relatively still. “GPCRs appear to be composed of two domains,” he explains. “The first four helices appear more rigid than the last three.”
In addition, the portions of the receptor sitting outside the cell membrane shifted their positions to accommodate the agonist binding, whereas the segments on the inside of the cell had smaller changes.
The greater flexibility for the outside portions may hold the key for understanding GPCRs’ ability to recognize and respond to molecules of many different sizes and shapes. This is reminiscent of how the immune system uses the antibody architecture to recognize so many different ligands.
“You need receptor diversity on the outside to recognize all the different ligands, but inside the cell, you need less diversity since the receptor signals via a smaller number of binding partners,” notes Dr. Stevens.