Nucleic Acids Research Advance Access originally published online on March 2, 2007
Nucleic Acids Research 2007 35(6):1933-1946; doi:10.1093/nar/gkl1104
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Nucleic Acids Research, 2007, Vol. 35, No. 6 1933-1946
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
The genomic HDV ribozyme utilizes a previously unnoticed U-turn motif to accomplish fast site-specific catalysis
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poner21Department of Chemistry, Single Molecule Analysis Group, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055, USA and 2Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic
*To whom correspondence should be addressed. Tel: +1-(734) 615-2060; Fax: +1-(734) 647-4865; Email: nwalter{at}umich.edu
Received September 5, 2006. Revised December 2, 2006. Accepted December 4, 2006.
The genome of the human hepatitis delta virus (HDV) harbors a self-cleaving catalytic RNA motif, the genomic HDV ribozyme, whose crystal structure shows the dangling nucleotides 5' of the cleavage site projecting away from the catalytic core. This 5'-sequence contains a clinically conserved U – 1 that we find to be essential for fast cleavage, as the order of activity follows U – 1 > C – 1 > A – 1 > G – 1, with a >25-fold activity loss from U – 1 to G – 1. Terbium(III) footprinting detects conformations for the P1.1 stem, the cleavage site wobble pair and the A-minor motif of the catalytic trefoil turn that depend on the identity of the N – 1 base. The most tightly folded catalytic core, resembling that of the reaction product, is found in the U – 1 wild-type precursor. Molecular dynamics simulations demonstrate that a U – 1 forms the most robust kink around the scissile phosphate, exposing it to the catalytic C75 in a previously unnoticed U-turn motif found also, for example, in the hammerhead ribozyme and tRNAs. Strikingly, we find that the common structural U-turn motif serves distinct functions in the HDV and hammerhead ribozymes.
Present address: M. V. Krasovska, Institute for Single Crystals, Academy of Science of Ukraine, Kharkov, Ukraine
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