Prostanoids, lipid metabolites involved in many processes in our bodies, transmit signals between cells by binding to G protein–coupled receptors (GPCRs) on cell surfaces. Due to the receptors’ wide-ranging roles in cells, drug developers have long wanted to target these GPCRs to treat conditions such as cancer and autoimmune diseases. But structural information about the receptors bound to their ligands has been limited because of the instability of the proteins.
Now a quartet of papers from three independent teams has been published in Nature Chemical Biology. Three of the papers report structures of the EP3 and EP4 receptors, which bind prostaglandin E2. The other paper reports structures of the TP receptor, which binds thromboxane A2.
The collection of structures is a “gold mine,” says Lawrence J. Marnett, a biochemist at Vanderbilt University who studies prostaglandins and wasn’t involved in the studies. “Extensive efforts have been made to develop agonists and antagonists for the various receptors, but most have only been useful as pharmacological probes, not as therapeutic agents,” he says. “This smorgasbord of structures for prostaglandin E2 and thromboxane A2 GPCRs defines the key molecular interactions responsible for ligand binding and should reenergize drug discovery efforts designed to exploit these receptors as targets.”
Each of the receptors sports the canonical GPCR structure with seven transmembrane helices. The ligand binding sites in the receptors are surprisingly small and completely enclosed. Surprisingly, the binding sites appear to be accessible through the side contacting the lipid membrane rather than through the top or bottom of the receptors.
“What’s beautiful about GPCRs is that although they have the same architecture, they are incredibly selective for so many different types of molecules,” says Raymond C. Stevens, a biochemist and structural biologist at the Bridge Institute at the University of Southern California. His team solved a structure of the EP3 receptor with the drug misoprostol, which is used to treat gastric ulcers and to induce labor (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0160-y). Stevens’ team used misoprostol to stabilize the receptor during purification and planned to exchange it for the natural ligand, but the receptor bound the drug so tightly that it couldn’t be displaced.
A team jointly led by Takuya Kobayashi and So Iwata of Kyoto University successfully solved a structure of the EP3 receptor with its endogenous ligand, prostaglandin E2 (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0171-8). In addition, they solved a structure of the EP4 receptor bound to an antagonist (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0131-3). That structure revealed that the antagonist binds to the receptor at the interface between the protein and the lipid bilayer.
Beili Wu of the Chinese Academy of Science and coworkers solved structures of the TP receptor bound to antagonists, ramatroban and daltroban, both of which are leads for the treatment of cardiovascular diseases (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0170). The team found that ramatroban binds to the TP receptor in a different way than it does to another prostanoid receptor, DP2. “Usually the same ligand binds to different GPCRs with similar binding modes,” Wu says. “Most of the key residues that interact with ramatroban in the TP structure are not conserved in DP2, indicating different ligand recognition mechanisms between these two receptors. This finding highlights the diversity of ligand-binding mechanisms of GPCRs.”