SMARTech Community: College of Sciences (CoS)

ProofReader, vol. 1, 2008

Mon, 29 Oct 2007 22:58:59 GMT

Title: ProofReader, vol. 1, 2008

Abstract: Included in this issue: What Makes a Math Department Great?; School of Mathematics History--The First 80 Years; Robert H. Kasriel (1918-2007) and Daniel A. Robinson (1932-2007) obituaries; Faculty, staff, and student profiles; Program news.

New RNA-binding peptidomimetic structures that repress HIV viral replication by specifically inhibiting transcriptional activation

Mon, 17 Mar 2008 22:58:59 GMT

Title: New RNA-binding peptidomimetic structures that repress HIV viral replication by specifically inhibiting transcriptional activation

Authors: Varani, Gabriele

Abstract: The Interaction between the human immunodeficiency virus (HIV-1) transactivator protein Tat and its response element TAR plays an essential role in viral replication by controlling HIV transcription. Previous attempts to inhibit this interaction have failed to yield molecules with sufficient potency and specificity to warrant pharmaceutical development. We have shown that comformationally constrained cyclic peptide structural mimics of Tat provide nM inhibitors of the Tat-TAR interaction. These peptidomimetics are proteolytically stable, penetrate cells efficiently and have no cytotoxicity. They specifically inhibit Tat-dependent activation of transcription in cells and repress replication of a wide variety of viral strains representing all the major HIV clades in primary human lymphocytes. The potency and selectivity observed for this family of peptides is unprecedented among Tat inhibitors and suggest that these types of compounds may be widely useful for the pharmacological inhibition of other protein-RNA interactions.

Description: Gabriele Varani, Professor of Chemistry and Professor of Biochemistry at the University of Washington, presented a lecture on Tuesday, March 18, 2008 at 11 am in Room 1116W of the Klaus Advanced Computing Building on the Georgia Tech Campus

RNA Enzymes: From Folding to Function in Living Cells

Mon, 24 Mar 2008 22:58:59 GMT

Title: RNA Enzymes: From Folding to Function in Living Cells

Authors: Fedor, Martha J.

Abstract: Our research aims to generate fundamental insights into catalysis by RNA enzymes and into the pathways through which RNAs form specific functional structures. RNA catalysis remains an intriguing puzzle that has grown in significance since the recent discoveries that the ribosome itself is an RNA enzyme and that human and bacterial mRNAs contain self-cleaving ribozymes. The hairpin ribozyme catalyzes a reversible self-cleavage reaction in which nucleophilic attack of a ribose 2’ hydroxyl on an adjacent phosphorus proceeds through a trigonal bipyramidal trasition state that leads to the formation of 2’,3’-cyclic phosphate and 2’ hydroxyl termini. The metal cation independence of activity and the availability of high-resolution active site structures have made the hairpin ribozyme the prototype for nucleobase-mediated catalytic chemistry. A network of stacking and hydrogen bonding interactions align the reactive phosphate in the appropriate orientation for an S_N2-type nucleophilic attack and orient nucleotide base functional groups near the reactive phosphate to facilitate catalytic chemistry. Two active site nucleobases, G8 and A38, adopt orientations reminiscent of the histidine residues that mediate general acid base catalysis in ribonuclease A, a protein enzyme that catalyzes the same phosphodiester cleavage chemistry. However, our biochemical experiments argue against analogous roles for G8 and A38 in hairpin ribozyme catalysis and suggest that these residues contribute to catalysis through positioning and orientation and electrostatic stabilization of the electronegative transition site. Ribozymes are useful model systems for investigation of RNA folding, since self-cleavage reflects the assembly of a precise functional structure. To learn how structure-function principles revealed through in vitro experiments translate to the behavior of RNA in living cells, we devised a way to evaluate RNA assembly in vivo using RNA self-cleavage rates to quantify assembly of functional RNA structures. Results of these studies show that intracellular RNA folding kinetics and equilibria are indistinguishable from RNA folding behavior in vitro, provided that in vitro folding reactions approximate the ionic conditions characteristic of an intracellular environment. These studies contribute basic knowledge of RNA structure and function and provide a framework for developing technical and therapeutic application involving RNAs as targets and reagents.

Description: Martha J. Fedor, Departments of Chemical Physiology and Molecular Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, presented a lecture on Tuesday, March 25, 2008, 11 AM in Room 1116W of the Klaus Advanced Computing Building on the Georgia Tech Campus

Structural studies of ribonucleoprotein complexes using molecular modeling

Wed, 05 Dec 2007 22:58:59 GMT

Title: Structural studies of ribonucleoprotein complexes using molecular modeling

Authors: Devkota, Batsal

Abstract: The current work reports on structural studies of ribonucleoprotein complexes, Escherichia coli and Thermomyces lanuginosus ribosomes, and Pariacoto virus (PaV) using molecular modeling. Molecular modeling is the integration and representation of the structural data of molecules as models. Integrating high-resolution crystal structures available for the E. coli ribosome and the cryo-EM density maps for the PRE- and POST- accommodation states of the translational cycle, I generated two all-atom models for the ribosome in two functional states of the cycle. A program for flexible fitting of the crystal structures into low-resolution maps, YUP.scx, was used to generate the models. Based on these models, we hypothesize that the kinking of the tRNA plays a major role in cognate tRNA selection during accommodation. Secondly, we proposed all-atom models for the eukaryotic ribosomal RNA. This is part of a collaboration between Joachim Frank, Andrej Sali, and our lab to generate an all-atom model for the eukaryotic ribosome based on a cryo-EM density map of T. lanuginosus available at 8.9Å resolution. Homology modeling and ab initio RNA modeling were used to generate the rRNA components. Finally, we propose a first-order model for a T=3, icosahedral, RNA virus called Pariacoto virus. We used the structure available from x-ray crystallography as the starting model and modeled all the unresolved RNA and protein residues. Only 35% of the total RNA genome and 88% of the protein were resolved in the crystal structure. The generated models for the virus helped us determine the location of the missing N-terminal protein tails. The models were used to propose a new viral assembly pathway for small RNA viruses. We propose that the basic N-terminal tails make contact with the RNA genome and neutralize the negative charges in RNA and subsequently collapse the RNA/protein complex into a mature virus. This process is reminiscent of DNA condensation by positively charged ions.