NEWS OF THE WEEK STRUCTURAL
BIOLOGY
soon as the relevant parts of NS2 and NS3 are synthesized, they come together and make the cut. SEEING DOUBLE Rice and coworkers show that this ; The catalytic simple model can't be right. They \ domain of the NS2-3 find that the catalytic domain of : protease of the the protease is actually a butterflyhepatitis C virus shaped dimer with two identical isadimerwith composite active sites. Ofthe three composite active key amino acids in each active site, sites. One monomer two comefromone monomer and is shown in blue and URRENT TREATMENTS FOR protease (Nature, DOI: 10.1038/ one comesfromthe other. the other in red. Although the dimer was a surthe hepatitis C virus, which nature04975). can cause cirrhosis and liver The structure is "eye opening," prise, it actually makes sense, accancer, are toxic with bad side ef- says Ralf Bartenschlager, a virolo- cording to Rice. "Why would you fects. Now, astructure ofahepatitis gist at the University of Heidel- encode proteolytic activity that C virus protease berg, in Germany. This study "may gets used right away for mediating that could be- redirect the interest of drug devel- a cleavage?" he asks. If proteolytic come a target for opers to this enzyme that has been activity is concentration dependent, "the dimer formation gives new drugs has largely neglected," he says. been revealed The hepatitis C virus's RNA you an added ability to regulate by virologists genome is translated into a single the cleavage." at Rockefeller polyprotein that must then be In addition to the dimer, the University. chopped into the virus's 10 com- structure also reveals that the Postdoctoral ponent proteins. Within this protease's C-terminal leucine associate Ivo C. polyprotein chain, the NS2-3 residue is "stuffed into the active Lorenz, research protease, which is made of parts site," Rice says, effectively turnLAB HOUNDS Marcotrigiano (from associate Joseph of the so-called nonstructural pro- ing off the enzyme after it cleaves left), Rice, Dentzer, and Lorenz, Marcotrigiano, teins 2 and 3, is responsible for a the protein. posing with Sadie the black lab, found visiting grad Although biochemical assays single cleavage between those two some surprises in the structure of student Thom- proteins. Although the protease have shown that the protease hepatitis C virus's NS2-3 protease. as G. Dentzer, includes parts of both NS2 and depends on zinc, there is no zinc and p r o f e s - NS3, the catalytic domain comes associated with the active site. Rice suspects that the zinc may sor Charles M. Rice report the fromNS2. structure of the catalytic domain The simplest model of the pro- be playing a structural role in the of the hepatitis C virus NS2-3 tease's activity suggests that as NS3 portion rather than a catalytic role. Raffaele De Francesco, a hepaHEALTH titis C expert at Merck's Institute for Research in Molecular Biology, Pomezia, Italy, predicts that DA has approved a sunscreen formula "availability of the structure of the & Development says, "The addition of a new infrom LOreal that includes the first new orelusive NS2-3 protease will triggredient is great, but this one is limited in scope ganic UV-blocking molecule the agency and only favors LOreal." David Steinberg, who ger intense research aimed at the has cleared since 1988. heads an eponymous consulting firm, says one design or discovery of inhibitors drawback of ecamsule is that it is water soluble of its proteolytic function.,, HowThe cosmetics company says the molecule, and thus not useful at the beach. ecamsule, is the only photo-stable filter apever, the way the enzyme inhibits proved in the U.S. for protection against short UVitself after a single cycle may make FDA approved avobenzone 18 years ago. Since A waves (320-340 nm). It will be used in a broad- then, ingredient makers have eagerly sought U.S. it challenging to interfere with the spectrum formula that also contains avobenzone approval of a new generation of improved organic enzyme's activity. and octocrylene, two previously approved filters. molecules for sun protection. European Union reg"In order to control this virus, ulators permit formulators to use 28 sunscreens, LOreal says the formula will protect users you're going to need a cocktail compared with the 17 now allowed in the U.S. from both UV-A, the wavelengths that can cause of specific antivirals," Rice says. skin cancer, and UV-B, the rays that cause skin to Many sunscreen-ingredient suppliers con"More targets with different resisburn. LOreal plans to offer the new formula, Anttend that FDA has been dragging its feet. LOreal's tance profiles are probably going helios SX, only in its own products, the first of ecamsule, for instance, was approved in Europe to be the way to go." The strucwhich will be a daily moisturizing cream to be inin 1991. And both Shaath and Steinberg point out ture of protease NS2-3 may give troduced in the fall. that other ingredients already accepted in Europe drug hunters yet another target—
PROTEASE REVELATION
Hepatitis C protease has dimer structure with composite active sites
c
U.S. Approves New Sunscreen
F
Consultant Nadim A. Shaath of Alpha Research 14
C & E N / JULY 3 1 , 2006
still await approval in the U.S.—MARC REISCH
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