NIH Research Provides Detailed View of Brain Protein Structure
Results may help improve drugs for neurological disorders (Oct. 11)National Institutes of Health (NIH) researchers have published the first highly detailed description of how neurotensin –– a neuropeptide hormone that modulates nerve-cell activity in the brain –– interacts with its receptor. Their findings suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs). The study was announced by the NIH on October 11 and was published in Nature.
"The knowledge of how the peptide binds to its receptor should help scientists design better drugs," said Dr. Reinhard Grisshammer, a scientist at the NIH's National Institute of Neurological Disorders and Stroke (NINDS). Binding of neurotensin initiates a series of reactions in nerve cells.
Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth.
Researchers used X-ray crystallography to show what the receptor looks like in atomic detail when it is bound to neurotensin. Their results provide the most direct and detailed views describing this interaction, which may change the way scientists develop drugs targeting similar neuropeptide receptors.
Neurotensin receptors and other GPCRs belong to a class of membrane proteins that are activated by a variety of molecules, called ligands. Previous X-ray crystallography studies showed that smaller ligands, such as adrenaline and retinal, bind in the middle of their respective GPCRs and well below the receptor’s surface. In contrast, Dr. Grisshammer’s group found that neurotensin binds to the outer part of its receptor, just at the receptor surface. These results suggest that neuropeptides activate GPCRs in a different way compared with the smaller ligands.
More work is needed to fully understand the detailed signaling mechanism of this GPCR, Dr. Grisshammer said.
For more information, visit the NIH Web site.