NEWS OF THE WEEK
WASABI RECEPTOR’S STRUCTURE SOLVED BIOMOLECULAR STRUCTURE: Ion
channel snapshot could lead to pain and itch remedies
A
WIDE VARIETY OF chemical irritants—includ-
NAT U R E
ing the molecules that give wasabi its kick and the toxic compounds that lend poison ivy its itch—activate the TRPA1 ion channel in the body. Switching on this channel leads to misery-producing pain, itch, or in the case of onions, tears. A structure of this important ion channel reported in Nature may pave the way to new analgesics that can tone down the protein when it signals too loudly (2015, DOI: 10.1038/ nature14367). “TRP” ion channels (pronounced “trip”) permit the passage of cations across cell membranes in plants, animals, and fungi. Humans have a whopping 27 different types of the channels. In 2013, David J. Julius and his colleagues at the University of California, San Francisco, used cryo-electron microscopy to solve the first structure of a member of this important family: TRPV1, which gets activated by capsaicin, the molecule that makes hot peppers hot. Julius’s team has now gotten a glimpse of TRPA1 using the same technique. Although the researchers’ 4-Å-resolution structure isn’t detailed enough to pinpoint individual atoms, it does provide general features of the protein’s shape in its closed, or “off,” conformation, Julius says. The team
found that four TRPA1 subunits assemble to form the ion channel and that this foursome requires an unusual phospholipid called inositol hexakisphosphate to be stable in cell membranes. The TRPA1 structure also revealed that 80% of the protein’s mass is located outside the channel’s membrane-spanning core, on either side of the cell membrane. Some of this mass is involved in binding a wide assortment of chemical irritants. Curiously, rather than forming typical transient bonds, certain compounds that trigger TRPA1 activate the channel by forming covalent bonds to some of its cysteine or lysine amino acid residues, says David E. Clapham of Harvard Medical
School in an associated commentary (Nature 2015, DOI: 10.1038/nature14383). Opening and closing of the TRPA1 pore is likely regulated, at least in part, by a collection of socalled ankyrin repeats, amino acid sequences that hang from the channel down into the cell’s interior and form a docking platform for regulator proteins, Julius says. This docking platform has “a propeller-like structure, resembling the backs of four armadillos,” Clapham adds. “In the future, more-detailed structures of TRPA1 in different conformations will reveal regulatory features, such as why the channel becomes sensitized and desensitized to calcium, and perhaps more importantly, how channel function can be blocked to treat asthma, inflammation, and pain,” Clapham notes.—SARAH EVERTS
Cryo-electron micrographs (left) of TRPA1, which is 104 Å wide, were used to construct the ribbon structure of the chemicalirritant-sensing ion channel.
PHARMACEUTICALS Bristol-Myers Squibb deal with uniQure focuses on cardiovascular disease Bristol-Myers Squibb and uniQure, a Dutch specialist in gene therapy, have formed a collaboration in which BMS will gain exclusive access to uniQure’s technology for use on multiple targets in cardiovascular disease. Gene therapy is a technique for correcting defective or missing genes by inserting a functional gene into the cells of a patient. The pact includes uniQure’s gene therapy program for congestive heart failure, which is intended to restore the heart’s ability to synthesize S100A1, a calcium sensor and regulator of heart function. Beyond cardiovascular disease, the
agreement includes potential collaboration on gene therapy for up to 10 targets. Under the terms of the agreement, uniQure will manage discovery efforts and be responsible for manufacturing clinical and commercial supplies using its insectcell-based production technique. BMS will take charge of development and regulatory activities and of commercialization. BMS will make a preliminary payment of about $100 million, which will cover the selection of three targets for research in addition to S100A1. UniQure could receive further R&D and regulatory milestone payments of hundreds of millions of dollars.
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Collaborating with uniQure “further strengthens our capability to bring forward transformational new therapeutics for difficult-to-treat diseases, including cardiovascular diseases,” says Carl P. Decicco, head of discovery research at BMS. Gene therapy has garnered the attention of other major pharmaceutical firms in recent months. Earlier this year Genzyme, the rare disease division of Sanofi, signed with Voyager Therapeutics to develop gene therapies for central nervous system diseases. And Pfizer began work in December with Spark Therapeutics on a gene therapy treatment for hemophilia B.—RICK MULLIN
