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RHODOPSIN REVELATION Crystal structure at 2.8-A resolution reveals details of transmembrane visual pigment

Ahigh-resolution X-ray structure of rhodopsin reveals some unex­pected features in the visual pig­

ment and confirms many others that re­searchers had deduced indirectly. Rho­dopsin—the protein in the retina that captures light, triggering a biochemical cascade that the brain interprets as sight—is the first member of the large and important family of G-protein-coupled receptors (GPCRs) to have its crystal structure determined.

The feat of determining rhodopsin's three-dimensional structure was accom­plished by a team including Krzysztof Palczewski, professor of chemistry and of ophthalmology and adjunct professor of pharmacology, and Ronald E. Sten-kamp, associate professor of biological structure, both at the University of Washington, Seattle; and Masashi Miya-no of the Structural Biophysics Labora­tory, RIKEN Harima Institute in Hyogo, Japan [Science, 289, 739 (2000)].

Like other GPCRs, rhodopsin is a transmembrane protein with seven char­acteristic a-helices that span the cell membrane. The molecules detect stimuli such as calcium ions, hormones, neuro­transmitters, or photons outside of a cell, then relay a signal to the cell's interior, where particular GTP-binding proteins (G-proteins) are activated. The receptors are prime targets for drug therapy.

Membrane proteins are notoriously difficult to coax into crystals good enough for X-ray structure studies. Rho­dopsin is especially tough: light causes its crystals to fall apart, even at 4 °C. "The field has been waiting for a crystal structure of rhodopsin for more than 20 years," comments Daniel Oprian, pro­fessor of biochemistry at Brandeis Uni­versity, Waltham, Mass., whose own re­search focuses on the structure and function of visual pigments.

Palczewski credits postdoc Tetsuji Okada for persevering until he found a successful way to grow high-quality rho­dopsin crystals [/. Struct. Biol, 130,73 (2000)]. Okada worked for two years in

Loops at the cytoplasmic (top) and extracellular (bottom) ends connect rhodopsin9s seven transmembrane a-hellces.

the lab's cold room in the dark. "You wouldn't find many people who could stand that," Palczewski tells C&EN.

Okada then took his most perfect crystals to synchrotron beam lines at

Stanford University; the Advanced Pho­ton Source at Argonne National Labora­tory; and the Japan Synchrotron Radia­tion Research Institute, Hyogo. The "bright" X-ray data allowed the re­searchers to obtain rhodopsin's struc­ture at a resolution of 2.8 A.

The "amazingly simple" arrangement of the three loops and carboxyl end that make up the cytoplasmic surface of rho­dopsin is one surprising aspect of the pro­tein's structure, Palczewski says. "The connecting loops are very short They are not sticking out like you'd expect in order to interact with a G-protein."

He points out, however, that the struc­ture reflects rhodopsin's inactive state, as it is in the dark. When light strikes the molecule, its chromophore—11-cis-retinal bound deep within the membrane-spanning helices—isomerizes to the all-trans configuration. And as the protein adjusts to the shifting shape of the chro­mophore, significant conformational changes likely are transmitted to the cy­toplasmic side.

The crystal structure proves correct many hypotheses about rhodopsin that had been previously developed. "Many key findings from extensive interdisci­plinary studies—mainly combining site-directed mutagenesis with biophysical approaches—seem to be confirmed," says Thomas P. Sakmar, Howard Hughes Medical Institute associate in­vestigator and head of the Laboratory of Molecular Biology & Biochemistry at Rockefeller University, New York City.

The rhodopsin structure probably will provide a reliable template for most of the other GPCRs, Oprian notes. "I be­lieve that the different receptors repre­sent relatively minor variations on a common evolutionary theme," he says.

Pamela Zurer

NSF Urged To Expand Science Awareness Expanding public awareness of science and engineering is a critical task for the National Science Foundation, concludes a committee of the National Science Board (NSB) that has been studying the issue. The committee's report on sci­ence communication by the agency was approved by NSB, the agency's govern­ing body, at its meeting last week in Ar­lington, Va.

"For the first time, NSF has recog­nized the need to communicate science and engineering," says M. R. C. Green­wood, chair of the NSB Committee on

Communication & Outreach. Green­wood, a professor of biology, is chancel­lor of the University of California, Santa Cruz. The effort, she says, will include public relations but also will encompass education and work with advocacy groups for science and engineering.

One such group, Greenwood says, is Research America, Alexandria, Va., whose efforts on behalf of biomedical research have helped to secure dramat­ic budget increases for the National In­stitutes of Health. Among other tactics, Research America uses results from

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public polling to influence congression­al appropriators.

The NSB report, says David L Schutt, assistant director of legislative and govern­ment affairs at the Ameri­can Chemical Society, re­inforces the need for simi­lar advocacy on behalf of the physical sciences and engineering. At a time when Congress has been holding steady or even cut­ting federal fiinding for the physical sciences and engi­neering, he says, "we need a Madison Avenue-type approach."

And efforts are under way to create an organiza­tion that will do just that, Greenwood Schutt continues. Under the direction of American Association for the Advancement of Science President Mary L Good, concerned members of the mathematics, physical sciences, and engi­neering communities have marshaled their resources to raise money and support for such an organization.

'The idea is to raise awareness and understanding," Schutt says. "People don't personally believe that science

and engineering have dramatically im­proved their lives."

Greenwood says there will be changes at NSF as a result of her committee's re­

port, which provides a se­ries of overarching rec­ommendations. For ex­ample, there will be assessments of the effec­tiveness of agency re­sources devoted to public awareness, she says, and there will likely be some internal reorganization aimed at increasing col­laborations across NSF directorates.

The use of metrics— public opinion polls, most likely—to assess gains in public under­

standing of science and engineering will move the effort beyond public relations.

"We will look at knowledge-base gains among the general public for sci­ence and engineering," for example, Greenwood says. "We will look at the importance parents place on science and math education. Those are measur­able outcomes."

William Schulz

BASF Takes On Takeda Vitamins BASF has reached an agreement to buy the worldwide bulk vitamin production and distribution assets of Japanese pharmaceutical maker Takeda and to form a 66% BASF-owned vitamins distri­bution venture in Japan.

The deal combines the $459 million bulk vitamins business of number-two worldwide producer BASF with num­ber-three Takeda's $220 million busi­ness. Roche leads the $2.3 billion indus­try, with just over $1 billion in 1999 vita­min sales.

The transaction will boost BASF's share of the bulk vitamin market from 20 to 30% at a cost somewhat below Osa­ka-based Takeda's annual vitamin sales, industry sources say. A BASF spokes­man would only say that the transaction was part of a company plan to invest $550 million to improve profits and strengthen BASFs competitive stance in the world vitamins business, now growing at 4% a year.

Some industry observers wonder if the BASF-Takeda agreement will raise eyebrows at regulatory agencies. Last year, BASF and Takeda agreed to pay

fines of $225 million and $72 million, re­spectively, to the U.S. for participating in a worldwide cartel to fix vitamin pric­es. The conspiracy included others such as Lonza, Merck KgA, and Degussa. Roche paid the biggest fine of all— $500 million. Former cartel members also face a European Union investiga­tion, and many have paid multi-million-dollar settlements to vitamin buyers and face additional suits in civil cases.

However, a BASF spokesman says

BASF gets a boost from Takeda's vitamins

BASF Oil soluble: A, E Water soluble: B-l, B-2, nicotin­amide, B-5, B-6, B-12, biotin, C Total 1999 sales: $459 million

Takeda Water soluble: B-l, B-2, B-6, folic acid, C Total 1999 sales: $220 million

Source: Company data

there is no link between the price-fixing scandal and the consolidation BASF would achieve when the expected deal with Takeda takes effect in early 2001, pending regulatory approvals. Both the BASF and Takeda boards of directors have approved the transaction. Chris­tian Dudeck, president of BASFs fine chemicals division, says, "We will lever­age the synergies arising from the com­bination of Takeda's competency in the water-soluble vitamins business and our strengths in the fat-soluble vitamins business" to garner a greater share of the market for BASF.

Hiroshi Uchiyama, president of Take­da's Vitamin & Food Co., says he is "con­fident" the combined businesses will lead to additional growth for the two parents. The BASF spokesman adds that low pric­es now characterize the competitive bulk vitamins market in which BASF hopes to grow through worldwide leadership in cost and technology.

While Takeda will hold the minority stake in the joint distribution operation in Japan, it will continue to produce and sup­ply vitamins exclusively to the joint ven­ture from its wholly owned Hikari plant in Yamaguchi, Japan. In addition to taking over Takeda's vitamin distribution busi­nesses in the U.S., Canada, Germany, and Singapore, BASF will also take over the Takeda vitamin plant in Wilmington, N.C., with associated vitamin manufac­turing technology and patents.

Marc Reisch

DuPont Settles Charges Related To Sulfuric Acid Release

DuPont has reached a $1.5 million agree­ment with the Justice Department and the Environmental Protection Agency to settle allegations related to a 1995 sulfiiric acid release at a Kentucky plant

The case is one of the first litigated under a section of the Clean Air Act that says companies have a general duty to maintain a safe facility, identify hazards that could lead to accidental releases, and minimize catastrophic releases. Congress added this provision, Section 112(r), to the Clean Air Act in response to the massive release in 1984 of methyl isocyanate from a Union Carbide plant in Bhopal, India.

The Justice Department says DuPont used cast-iron pipe in a tank used to store

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