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Tertiary contacts distant from the active site prime a ribozyme for catalysis
Monika Martick1, William G Scott
1Department of Molecular, Cellular and Developmental Biology, Robert L. Sinsheimer Laboratories, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
Cell
|July 25, 2006
Summary
A new crystal structure of the Schistosoma mansoni hammerhead ribozyme reveals how remote tertiary interactions enhance catalysis by 1000-fold. This finding resolves contradictory mechanistic explanations for ribozyme activity.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Hammerhead ribozymes are crucial RNA enzymes with complex catalytic mechanisms.
- Previous studies using crystallography and biochemical analyses yielded conflicting explanations for hammerhead ribozyme catalysis.
Purpose of the Study:
- To elucidate the structural basis for the catalytic enhancement of the full-length Schistosoma mansoni hammerhead ribozyme.
- To reconcile contradictory mechanistic models of hammerhead ribozyme activity.
Main Methods:
- X-ray crystallography at 2.2 A resolution was used to determine the structure of the full-length hammerhead ribozyme.
- Biochemical analyses were integrated with structural data.
Main Results:
- The crystal structure revealed tertiary interactions remote from the active site that are critical for catalysis.
- Specific nucleotide positions (G-12, G-8) support proposed acid-base catalysis roles.
- The structure clarifies the alignment of the nucleophile and scissile phosphate, explaining catalytic efficiency.
- A novel fold was identified, accommodating previous experimental findings and explaining previously unclear nucleotide roles.
Conclusions:
- The presented structure provides a unified and unambiguous explanation for hammerhead ribozyme catalysis.
- Tertiary interactions play a significant role in priming the ribozyme for enhanced catalytic activity.
- This work resolves long-standing discrepancies in the mechanistic understanding of hammerhead ribozymes.
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