Structural basis for Diels-Alder ribozyme-catalyzed carbon-carbon bond formation

Alexander Serganov, Sonja Keiper, Lucy Malinina, Valentina Tereshko, Eugene Skripkin, Claudia Höbartner, Anna Polonskaia, Anh Tuân Phan, Richard Wombacher, Ronald Micura, Zbigniew Dauter, Andres Jäschke, Dinshaw J. Patel

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

The majority of structural efforts addressing RNA's catalytic function have focused on natural ribozymes, which catalyze phosphodiester transfer reactions. By contrast, little is known about how RNA catalyzes other types of chemical reactions. We report here the crystal structures of a ribozyme that catalyzes enantioselective carbon-carbon bond formation by the Diels-Alder reaction in the unbound state and in complex with a reaction product. The RNA adopts a λ-shaped nested pseudoknot architecture whose preformed hydrophobic pocket is precisely complementary in shape to the reaction product. RNA folding and product binding are dictated by extensive stacking and hydrogen bonding, whereas stereoselection is governed by the shape of the catalytic pocket. Catalysis is apparently achieved by a combination of proximity, complementarity and electronic effects. We observe structural parallels in the independently evolved catalytic pocket architectures for ribozyme- and antibody-catalyzed Diels-Alder carbon-carbon bond-forming reactions.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalNature Structural and Molecular Biology
Volume12
Issue number3
DOIs
StatePublished - 2005

Bibliographical note

Funding Information:
We gratefully acknowledge support by the US National Institutes of Health, the DeWitt Wallace Foundation and the Abby Rockefeller Mauze Trust (D.J.P.), the Bundesministerium für Bildung und Forschung (BioFuture program), the Deutsche Forschungsgemeinschaft, HFSP and the Fonds der Chemischen Industrie (A.J.), and the Austrian Science Fund FWF (R.M.). We thank V. Kuryavyi for extensive discussions on graphic programs, A. Teplov for help with data collection, M. Becker and the staff of the X25 and X12c beamlines at National Synchrotron Light Source for assistance with data collection, and the personnel of beamlines 14-BM and 19-BM at the Advanced Photon Source for data collection support.

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