Neuropeptide Receptor Secrets Uncovered In Atomic Level Images
Atomic level x-ray crystallography images were used by NIH scientists to show how the neuropeptide hormone neurotensin might activate its receptors. The description is the first of its kind for a neuropeptide-binding G protein-coupled receptor (GPCR), a class of receptors involved in a wide range of disorders, and the target of many drugs.
Binding to receptors on a cell’s exterior surface is how many hormones and neurotransmitters work. Binding activates receptors, causing them to twist, turn and spark chemical reactions inside cells.
“G protein-coupled receptors are found throughout the body. Knowing how they work should help scientists devise better treatments.”
The neuropeptide neurotensin is believed to be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth. In previous work, Dr. Grisshammer and his colleagues demonstrated how neurotensin binds to the part of its receptor located on a cell’s surface.
In this study, they show how binding alters the structure of the rest of the receptor, which passes through a cell’s membrane and into its interior. There neurotensin receptors activate G proteins, a group of molecules inside cells that controls a series of chemical chain reactions.
Using the GM/CA-CAT beamline at the Advanced Photon Source of the Argonne National Laboratory, researchers beamed X-rays at crystallized neurotensin receptor molecules. This is unusual, since producing crystals of receptors which activate G proteins is challenging, and in most exissting studies, scientists have investigated inactive receptors.
“The receptor we crystallized is very close to the active form found in nature,” said Dr. Grisshammer. “We may have the first picture of a peptide-binding G protein-coupled receptor just before it engages with the G protein.”
The scientists made multiple genetic modifications to a less active version of the neurotensin receptor they had used before, in order To achieve these results. Experiments performed in test tubes showed that mixing the receptor with neurotensin sparked the G protein reactions for which the scientists were looking.
The G Protein Drawbridge
When the scientists looked at the structure of the new crystals, they found how binding of neurotensin to the receptor caused critical parts of the receptor located below a cell’s surface to change shape.
In particular, they saw that a region in the middle of the receptor dropped like a draw bridge to link the neurotensin binding site to parts of the receptor found inside cells that are important for G protein activation. The scientists concluded that this change may prepare the receptor for activating G proteins.
“For years scientists have made educated guesses about how peptide receptors work. Now we may finally know,” said Dr. Grisshammer.
He plans to continue the work to fully understand how neurotensin and other G protein-coupled receptors translate messages delivered by neuropeptides into reactions inside cells.