NEWS OF THE WEEK STRUCTURAL
BIOLOGY
FLIP-FLOPPED STRUCTURE Finding suggests mechanism for how protein pumps drugs out of cells
P
ROTEINS THAT PUMP DRUGS
out of bacterial cells contribute to the problem of multidrug resistance in diseases such as tuberculosis. New research findings may help lead to a solution to this problem. Geoffrey Chang and coworkers at Scripps Research Institute report the X-ray crystal structure at 3.7-Â resolution of one of these proteins in action—the EmrE protein from Escherichia coli bound to the arsonium analog of tetraphenylphosphonium, one of the drugs EmrE transports {Science 2005,310,1950). EmrE makes bacteria resistant to tetracycline, ethidium, and other cationic antibiotics. Developing inhibitors of such protein pumps could make old drugs effective again. T h i s m e m b r a n e protein is a homodimer made of two chemically but not structurally identical polypeptides that align themselves in an inverted, antiparallel fashion. Although these subunits have the same amino acid sequence, they adopt different conformations, making the protein asymmetric. Each subunit is composed of four helices. T h e arrangement of the first three helices is nearly identical in each subunit; the fourth helix, however, is packed differently. T h e difference between the four helices is "the structural basis for the asymmetry and also explains how the [drug] transporter could have a function that's unidirectional," Chang says. Although this asymmetric arr a n g e m e n t was predicted by a cryo-electron-microscopic analysis of 2-D EmrE crystals, "this is the first convincing demonstration of the phenomenon," says Chris Tate, WWW.CEN-0NLINE.ORG
a structural biologist at the M R C Laboratory of Molecular Biology, Cambridge, England. T h e earlier c r y o - E M w o r k suggested a similar but not identical structure for EmrE. "I think they're seeing t h e t r a n s p o r t e r in one conformation, and we're seeing it in another," Chang says. "That's great for biology because then you can actually form a biological story between the two." In the current paper, Chang and his coauthors write, "interconversion of the EmrE transporter between these t w o (and perhaps other) conformations may drive drug transport." T h e X-ray structure reveals the location of two glutamates
GOVERNMENT
&
t h a t have p r e v i ously been shown through biochemical experiments to be essential for drug efflux. These glutamates have previously been proposed to contact the drug simultaneously, but Chang believes that the drug is handed off from one glutamate to the other. "It's going to take some time to figure this out from a biochemical aspect," he says. "The structural information is very compelling for this type of mechanism." "From a biological perspective, the most remarkable contribution of this paper is that it unambiguously shows that functional antiparallel homodimers of membrane proteins are indeed possible," says I b a n Ubarretxena-Belandia, a structural biologist at City University of N e w York. "Although such an arrangement might not be generalized in nature, it raises fundamental questions for membrane protein biosynthesis and structure."—CELIA ARNAUD
DRUG PUMP EmrE is an inverted, asymmetric homodimer consisting of two subunits (red and blue) with identical amino acid sequences but slightly different structures. The protein is shown bound to its substrate (green). A key glutamate residue is shown in yellow. COURTESY OF GEOFFREY CHANG
POLICY
Senate Rejects Arctic Drilling Bid
A
dvocates of oil and natural gas development in the Arctic National Wildlife Refuge (ANWR) are promising to renew their efforts in the coming months after the Senate on Dec. 21 narrowly rejected a provision that would have authorized exploration and drilling on Alaska's northern coastal plain. A Democratic-led filibuster blocked an attempt by drilling supporters to include ANWR leasing in the fiscal 2006 Defense Department appropriations bill. Republicans fell several votes short of the 60 needed to cut off debate on the legislation. ANWR, which is estimated to hold as much as 10 billion barrels of oil, has been the subject of a bitter battle in Congress for more than two decades. Drilling supporters say they will continue to fight. "This issue is too important to accept defeat," says Senate Energy & Natural Resources Committee Chairman Pete V. Domenici (R-N.M.). He says he will put the ANWR drilling language in filibuster-proof budget legislation in the spring. "ANWR remains one of my top priorities. De-
veloping more of our own energy is the right thing to do for our economy, our consumers, and our security. I'm not walking away from this challenge," Domenici says. Drilling opponents insist the refuge and its assortment of wildlife should be protected. "We stopped drilling in the Arctic for now, but we will remain vigilant to make sure the country focuses on real solutions to our over dependence on foreign oil and not Christmas packages for the oil companies," says Sen. Maria Cantwell (D-Wash.). After the vote, American Chemistry Council President Jack N. Gerard urged lawmakers to address the nation's "unfinished" energy agenda. "While opening ANWR to exploration would result in new, much-needed energy resources a decade from now, American consumers and businesses are being hit today by an immediate energy problem: soaring natural gas prices and impending supply shortages," he notes. "Congress must come to grips with our nation's long-term and short-term energy needs."—GLENN HESS
C & E N / J A N U A R Y 2, 2 0 0 6
9
