DAMAGE-FREE GLIMPSE OF PHOTOSYNTHESIS CRYSTALLOGRAPHY: Work corrects
the oxidation state of Mn atoms in photosystem II’s catalytic center APANESE RESEARCHERS have solved a new
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crystal structure of photosystem II (PSII) using an X-ray free-electron laser (Nature 2014, DOI: 10.1038/nature13991). The structure, free of radiationderived artifacts associated with previous structures of PSII, could help in the design of artificial water-oxidation catalysts for energy applications. The structure of PSII—the protein complex in plants and other photosynthetic organisms that catalyzes the oxidation of water during photosynthesis— has previously been solved using conventional X-ray diffraction. But those methods are thought to damage the Mn4CaO5 cluster that is the catalytic heart of PSII. Free-electron lasers avoid such radiation damage. Solved by a team led by Jian-Ren Shen of Okayama University and Masaki Yamamoto and Hideo Ago of RIKEN, the new 1.95-Å structure is of PSII from the cyanobacterium Thermosynechococcus vulcanus. It reveals
RARE DISEASE FIRMS MERGE BIOTECHNOLOGY: BioMarin’s purchase
of Prosensa is next twist in race to get muscular dystrophy drug approved N A RISKY but potentially profitable deal, orphan
I
disease drug specialist BioMarin Pharmaceutical will pay $680 million to acquire Prosensa, a Dutch biotech firm with a late-stage compound to treat Duchenne muscular dystrophy (DMD), a rare, fatal disease. Prosensa shareholders could get another $160 million if the drug, drisapersen, gets approved in both the U.S. and Europe. The deal adds yet another twist in the race to get a treatment for DMD, which affects only males, to market. Prosensa is neck and neck with Sarepta Therapeutics, a Cambridge, Mass.-based biotech that is developing its own DMD drug, eteplirsen. Both drugs use antisense technology that enables the production of a shortened version of dystrophin, a critical protein that is missing from the muscles of boys with DMD. Drisapersen could become the biggest product in BioMarin’s portfolio, the firm’s CEO, Jean-Jacques Bienaimé,
distances between catalytic Mn atoms that are about 0.1 to 0.2 Å shorter than those found using conventional X-ray diffraction. The new structure also suggests that two of the Mn atoms are in the +4 oxidation state, and the other two are in the +3 oxidation state. Earlier estimates suggest that the X-ray dose used in the conventional method may have caused some of the Mn atoms to be reduced to the +2 oxidation state. The oxygen atoms bridge the Mn atoms. One of the oxygen atoms has significantly longer bonds to Mn atoms than do the other oxygen atoms. The new structure confirms that those longer bonds are not an artifact of radiation damage. The researchers think that that oxygen is part of a hydroxide ion from the substrate water. The finding “represents significant progress” in understanding the structure and workings of PSII, says Michael Haumann, a physicist at the Free University of Berlin who has studied PSII’s structure. The structure confirms the overall geometry previously reported while revealing interesting differences that might be relevant to the catalytic mechanism. “This structure is expected to serve as an important input to theoretical studies aiming at the mechanism of water oxidation.”—CELIA ARNAUD
Photosystem II exhibits longer bonds to the yellow O atom than those to the red O atoms. This hints at Mn atoms being in the +3 and +4 oxidation states. Bond distances are in angstroms.
said in a presentation discussing the acquisition. But drisapersen has a checkered past: GlaxoSmithKline licensed the drug in 2009, only to return it to Prosensa earlier this year after a Phase III study failed to prove it could help boys with ROLLER COASTER DMD walk better. Prosensa argues that data Prosensa’s Duchenne muscular from a smaller Phase II study suggest the drug dystrophy drug drisapersen helps boys with less-advanced disease. has seen some ups and downs FDA is allowing Prosensa to file for apover the past five years. proval of drisapersen—a process the compaOctober 2009 GlaxoSmithKline ny began in October—but it is requiring two (GSK) licenses drisapersen from additional studies. If the results from those Prosensa. trials come back negative, the drug could be September 2013 The pulled from the market. compound fails a Phase III study. Although BioMarin went to great pains in January 2014 GSK returns its presentation to make the case for approvrights to Prosensa. al of drisapersen based on existing data, inJune 2014 FDA tells Prosensa it dustry watchers see significant uncertainty. can file for approval but will need “We think there is much risk,” Cowen & Co. to conduct two more studies. stock analyst Phil Nadeau wrote in a note to October 2014 Prosensa begins investors. With two failed studies, “there a a New Drug Application. good chance that the regulators require anNovember 2014 BioMarin other Phase III prior to approval.” agrees to acquire Prosensa. But Nadeau also points out that the potential rewards are great: Because DMD has no approved treatment, the market for drisapersen could be as much as $3 billion per year.—LISA JARVIS
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DECEMBER 1, 2014
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