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Plos Biology : Capturing Hammerhead Ribozyme Structures in Action by Modulating General Base Catalysis, Volume 6

By Chi, Young-in

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Book Id: WPLBN0003928769
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Capturing Hammerhead Ribozyme Structures in Action by Modulating General Base Catalysis, Volume 6  
Author: Chi, Young-in
Volume: Volume 6
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Historic
Publication Date:
Publisher: Plos

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Chi, Y. (n.d.). Plos Biology : Capturing Hammerhead Ribozyme Structures in Action by Modulating General Base Catalysis, Volume 6. Retrieved from http://www.ebooklibrary.org/


Description
Description : PDZ domains are protein–protein interaction modules that recognize specific C-terminal sequences to assemble protein complexes in multicellular organisms. By scanning billions of random peptides, we accurately map binding specificity for approximately half of the over 330 PDZ domains in the human and Caenorhabditis elegans proteomes. The domains recognize features of the last seven ligand positions, and we find 16 distinct specificity classes conserved from worm to human, significantly extending the canonical two-class system based on position 2. Thus, most PDZ domains are not promiscuous, but rather are fine-tuned for specific interactions. Specificity profiling of 91 point mutants of a model PDZ domain reveals that the binding site is highly robust, as all mutants were able to recognize Cterminal peptides. However, many mutations altered specificity for ligand positions both close and far from the mutated position, suggesting that binding specificity can evolve rapidly under mutational pressure. Our specificity map enables the prediction and prioritization of natural protein interactions, which can be used to guide PDZ domain cell biology experiments. Using this approach, we predicted and validated several viral ligands for the PDZ domains of the SCRIB polarity protein. These findings indicate that many viruses produce PDZ ligands that disrupt host protein complexes for their own benefit, and that highly pathogenic strains target PDZ domains involved in cell polarity and Growth. We have obtained precatalytic (enzyme–substrate complex) and postcatalytic (enzyme–product complex) crystal structures of an active full-length hammerhead RNA that cleaves in the crystal. Using the natural satellite tobacco ringspot virus hammerhead RNA sequence, the self-cleavage reaction was modulated by substituting the general base of the ribozyme, G12, with A12, a purine variant with a much lower pKa that does not significantly perturb the ribozyme’s atomic structure. The active, but slowly cleaving, ribozyme thus permitted isolation of enzyme–substrate and enzyme–product complexes without modifying the nucleophile or leaving group of the cleavage reaction, nor any other aspect of the substrate. The predissociation enzyme-product complex structure reveals RNA and metal ion interactions potentially relevant to transition-state stabilization that are absent in precatalytic structures.

 

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