UNC and UCSF labs create a new research tool to find homes for two orphan cell-surface receptors, a crucial step toward finding better therapeutics and causes of drug side effects.
CHAPEL HILL, NC – Our cells are constantly communicating, using neurotransmitters and hormones to signal to each other. Molecular receptors on each cell receive these chemical signals and allow cells to accomplish a task important for health. Astonishingly, for about half of these receptors, the chemical signals remain unknown. These “orphan receptors” are highly expressed in particular tissues but their functions remain a mystery. They are considered “dark” elements of the genome, and yet they hold great potential for drug development for a variety of diseases and conditions.
Now, scientists at the University of North Carolina School of Medicine (UNC) and University of California, San Francisco (UCSF) have created a general tool to probe the activity of these orphan receptors, illuminating their roles in behavior and making them accessible for drug discovery. The creation of the research tool – which involves computer modeling, yeast- and mammalian cell-based molecular screening techniques, and mouse models – was published today in the journal, Nature.
Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the Department of Pharmacology is co-senior author of the Nature paper along with Brian Shoichet, PhD, professor of pharmaceutical chemistry at UCSF. Xi-Ping Huang and Wesley Kroeze, both Research Assistant Professors in the Roth Lab are co-first authors on the Nature paper, along with Joel Karpiak of UCSF.
(above excepts from full article on UNC School of Medicine Newsroom by mark.derewicz@unch.unc.edu published Nov. 9, 2015)
Read the article in Nature, 527(7579): 477-83, doi: 10.1038/nature15699.
Abstract from the article:
At least 120 non-olfactory G-protein-coupled receptors in the human genome are ‘orphans’ for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.