news of the week JANUARY 11, 2016 EDITED BY MITCH ANDRÉ GARCIA & MANNY I. FOX. MORONE
FIRST DNAZYME STRUCTURE OBTAINED
F
CLAUDIA HÖBARTNER
this is the first one. It’s really cool to see DNA catalyzing a reaction like this.” “Many groups have tried to provide a crystal structure of a DNAzyme for the past two decades, and finally one has succeeded,” says functional nucleic acid specialist Yingfu Li of McMaster University. Mutagenesis studies had provided STRUCTURAL BIOLOGY: Long-sought evidence suggesting that folded conformation reveals synthetic indirect single-stranded DNAzymes are ca“I know from personal catalyst’s probable mechanism pable of adopting intricate tertiary experience how hard it’s folds like those of enzymes and ribeen to get a DNAzyme bozymes—RNA enzymes—to form structure, and this is the OR ABOUT TWO DECADES, chemists have been well-defined catalytic active sites. first one. It’s really cool synthesizing libraries of single-stranded DNAs But this study is the first to make it and screening them for ones that can catalyze crystal clear, Li says. to see DNA catalyzing specific reactions. Scientists think these DNA enScott K. Silverman of the Unia reaction like this.” zymes, or DNAzymes, could serve versity of Illinois, Urbana—GERALD F. JOYCE, SCRIPPS RESEARCH INSTITUTE CALIFORNIA as medical diagnostics, functional Champaign, who first components in nanotechnologies, identified 9DB1 and or even drugs. In fact, some have was Höbartner’s postdoc adviser, been tested in clinical trials, but none notes that the mechanistic analysis have yet been approved. reveals how the positioning of But until now, researchers haven’t key nucleotide pairs in 9DB1 been able to obtain a crystal structure or enables it to catalyze 3’ to 5’ determine a catalytic mechanism for any RNA ligation rather than DNAzyme. By sheer persistence, Clau2’ to 5’ ligation. dia Höbartner, Vladimir Pena, and coThe study also highlights workers at the Max Planck Institute for a difference between Biophysical Chemistry and Georg-August ribozymes and DNAUniversity found the right conditions zymes. Ribozymes to crystallize and structurally use RNA’s 2’-hydroxyl analyze a DNAzyme called 9DB1 groups, which are absent that stitches together, or ligates, in DNA, for structural inRNA strands (Nature 2016, DOI: teractions or directly for 10.1038/nature16471). catalysis. The new strucThey succeeded by crysture shows why the lack tallizing a form of 9DB1 in of these groups doesn’t which its reaction product, diminish the catalytic aca ligated RNA, is still attivity of DNAzymes. The tached. The structure en- Crystal structure of the DNAzyme 9DB1 (blue) after missing hydroxyls make completing a reaction and with its RNA ligation abled the researchers to DNA’s sugar-phosphate propose the first molecu- product (orange, with red ligation point) still bound. backbone more flexible, Flat polygons are nucleotide sugars and bases. lar mechanism of action allowing acrobatic conforfor any DNAzyme. mations that compensate The work could help researchers begin to rationally for the absent hydroxyls in DNAzymes. design DNAzymes to improve their catalytic activHöbartner admits that the study could have provided ity or change their substrate selectivity. Indeed, the more mechanistic information if the DNAzyme had Höbartner-Pena team revised 9DB1’s substrate selecbeen caught prior to or during catalysis, as such confortivity as part of the study. mations are more mechanistically revelatory. “Our next “It’s the missing piece,” says Gerald F. Joyce of goals are to obtain a structure of 9DB1’s precatalytic Scripps Research Institute California, who, with Ronstate and to get further insights into the mechanism,” ald R. Breaker of Yale University, discovered the first she says. She and others in the field also hope eventually DNAzyme in 1994. “I know from personal experience to structurally analyze other DNAzymes and compare how hard it’s been to get a DNAzyme structure, and their mechanisms with that of 9DB1.—STU BORMAN CEN.ACS.ORG
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JANUARY 11, 2016
