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Crystal Structure of the Catalytic Core of an RNA-Polymerase Ribozyme

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Science  27 Nov 2009:
Vol. 326, Issue 5957, pp. 1271-1275
DOI: 10.1126/science.1174676

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Revealing the RNA World?

The RNA World hypothesis posits that at an early step in the appearance of life, RNA acted both as an information storage molecule and as an enzyme—or ribozyme. Such dual functionality would allow for an RNA species that could replicate itself and thus seed the beginning of molecular evolution. The involvement of RNA in a number of fundamental cell biological processes, together with its ability, either naturally or through in vitro evolution, to catalyze a range of chemical reactions, provides some indirect support for this view. Shechner et al. (p. 1271) have now determined the structure of an in vitro–evolved RNA ligase ribozyme that catalyses a chemical reaction essentially identical to that of proteins that replicate RNA. The active site of the RNA ligase could be superimposed upon that of the protein enzyme to reveal analogous residues important for the catalytic joining of RNA moieties. These findings will help in the engineering of more effective ribozyme polymerases.

Abstract

Primordial organisms of the putative RNA world would have required polymerase ribozymes able to replicate RNA. Known ribozymes with polymerase activity best approximating that needed for RNA replication contain at their catalytic core the class I RNA ligase, an artificial ribozyme with a catalytic rate among the fastest of known ribozymes. Here we present the 3.0 angstrom crystal structure of this ligase. The architecture resembles a tripod, its three legs converging near the ligation junction. Interacting with this tripod scaffold through a series of 10 minor-groove interactions (including two A-minor triads) is the unpaired segment that contributes to and organizes the active site. A cytosine nucleobase and two backbone phosphates abut the ligation junction; their location suggests a model for catalysis resembling that of proteinaceous polymerases.

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