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@article{1299596, author = {Sripathi, Kamali N. and Banáš, Pavel and Réblová, Kamila and Šponer, Jiří and Otyepka, Michal and Walter, Nils G.}, article_location = {CAMBRIDGE}, article_number = {8}, doi = {http://dx.doi.org/10.1039/c4cp05083e}, keywords = {HEPATITIS-DELTA-VIRUS; SELF-CLEAVING RIBOZYMES; ACID-BASE CATALYSIS; MOLECULAR-DYNAMICS; CONFORMATIONAL SWITCH; CLEAVAGE ACTIVITY; METAL-ION; MECHANISTIC CHARACTERIZATION; CRYSTAL-STRUCTURE; GENOMIC RIBOZYME}, language = {eng}, issn = {1463-9076}, journal = {Physical Chemistry Chemical Physics}, title = {Wobble pairs of the HDV ribozyme play specific roles in stabilization of active site dynamics}, url = {http://pubs.rsc.org/en/content/articlepdf/2015/cp/c4cp05083e}, volume = {17}, year = {2015} }
TY - JOUR ID - 1299596 AU - Sripathi, Kamali N. - Banáš, Pavel - Réblová, Kamila - Šponer, Jiří - Otyepka, Michal - Walter, Nils G. PY - 2015 TI - Wobble pairs of the HDV ribozyme play specific roles in stabilization of active site dynamics JF - Physical Chemistry Chemical Physics VL - 17 IS - 8 SP - 5887-5900 EP - 5887-5900 PB - ROYAL SOC CHEMISTRY SN - 14639076 KW - HEPATITIS-DELTA-VIRUS KW - SELF-CLEAVING RIBOZYMES KW - ACID-BASE CATALYSIS KW - MOLECULAR-DYNAMICS KW - CONFORMATIONAL SWITCH KW - CLEAVAGE ACTIVITY KW - METAL-ION KW - MECHANISTIC CHARACTERIZATION KW - CRYSTAL-STRUCTURE KW - GENOMIC RIBOZYME UR - http://pubs.rsc.org/en/content/articlepdf/2015/cp/c4cp05083e L2 - http://pubs.rsc.org/en/content/articlepdf/2015/cp/c4cp05083e N2 - The hepatitis delta virus (HDV) is the only known human pathogen whose genome contains a catalytic RNA motif (ribozyme). The overall architecture of the HDV ribozyme is that of a double-nested pseudoknot, with two GU pairs flanking the active site. Although extensive studies have shown that mutation of either wobble results in decreased catalytic activity, little work has focused on linking these mutations to specific structural effects on catalytic fitness. Here we use molecular dynamics simulations based on an activated structure to probe the active site dynamics as a result of wobble pair mutations. In both wild-type and mutant ribozymes, the in-line fitness of the active site (as a measure of catalytic proficiency) strongly depends on the presence of a C75(N3H3+)N1(O5') hydrogen bond, which positions C75 as the general acid for the reaction. Our mutational analyses show that each GU wobble supports catalytically fit conformations in distinct ways; the reverse G25U20 wobble promotes high in-line fitness, high occupancy of the C75(N3H3+)G1(O5') general-acid hydrogen bond and stabilization of the G1U37 wobble, while the G1U37 wobble acts more locally by stabilizing high in-line fitness and the C75(N3H3+)G1(O5') hydrogen bond. We also find that stable type I A-minor and P1.1 hydrogen bonding above and below the active site, respectively, prevent local structural disorder from spreading and disrupting global conformation. Taken together, our results define specific, often redundant architectural roles for several structural motifs of the HDV ribozyme active site, expanding the known roles of these motifs within all HDV-like ribozymes and other structured RNAs. ER -
SRIPATHI, Kamali N., Pavel BANÁŠ, Kamila RÉBLOVÁ, Jiří ŠPONER, Michal OTYEPKA a Nils G. WALTER. Wobble pairs of the HDV ribozyme play specific roles in stabilization of active site dynamics. \textit{Physical Chemistry Chemical Physics}. CAMBRIDGE: ROYAL SOC CHEMISTRY, roč.~17, č.~8, s.~5887-5900. ISSN~1463-9076. doi:10.1039/c4cp05083e. 2015.
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