The 3rd International Conference

Transcription

1 The 3rd International Conference on Nucleic Acid-Protein Chemistry and Structural Biology for Drug Discovery Place: Petit Science Center (Room 101 PSC, 100 Piedmont Ave. SE, Atlanta, GA 30303) Time: September 14-15, 2013 (Starting at 7:30 am) Organizer & Chair: Zhen Huang Committee Members: Andrzej Joachimiak, Bi-Cheng Wang, Binghe Wang, David Wilson, Sibo Jiang, Wen Zhang Sponsors: GSU, NSF, CAPA, SeNA L S G Opening Speech: Dr. Mark Becker (President of ) Keynote Speech: Dr. Thomas Steitz (Nobel Laureate in Chemistry, 2009) Speakers: Margo A. Brinton Robert T. Batey Martin Egli Eric Ennifar Markus Germann Ichiro Hirao Zhen Huang Li-Wei Hung Andrzej Joachimiak Jeffrey Kieft Paul Langan Gaohua Liu David Lynn Suresh Srivastava Bi-Cheng Wang Irene Weber Loren Williams David Wilson Bo Xiao Wen Zhang C A P A

2 The 3 rd International Conference on Nucleic Acid-Protein Chemistry and Structural Biology for Drug Discovery Place: Petit Science Center (Room 101 PSC, 100 Piedmont Ave. SE, Atlanta, GA 30303) Time: September 14-15, 2013 (starting at 7:30 am with registration and continental breakfast) Organizer & Chair: Zhen Huang Committee Members: Andrzej Joachimiak, Bi-Cheng Wang, Binghe Wang, David Wilson, Sibo Jiang, Wen Zhang

3 2 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY Science is Art.

4 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY 3 The 3 rd International Conference on Nucleic Acid-Protein Chemistry and Structural Biology for Drug Discovery Place: Petit Science Center (Room 101 PSC, 100 Piedmont Ave. SE, Atlanta, GA 30303) Time: September 13-15, 2013 Organizer & Chair: Zhen Huang Committee Members: Andrzej Joachimiak, Bi-Cheng Wang, Binghe Wang, David Wilson, Sibo Jiang, Wen Zhang Contents Program 4 Abstracts.. 6 Sponsors 48

5 4 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY Curiosity leads to Discovery.

6 4 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY Friday, Sep. 13, 2013 Conference Agenda 17:00 21:00 Registration, Check-in, Reception/Pizza Dinner, Poster Session, and Social Hours Saturday, Sep. 14, 2013 Chair: Margo Brinton 7:30 8:00 am Registration & Continental Breakfast 8:00 8:15 Opening Speech: Mark Becker (President of ) 8:15 9:00 Keynote Speech: Thomas Steitz (Nobel Laureate in Chemistry, 2009) 9:00 9:30 9:30 10:00 David Wilson One DNA Minor Groove Many Possibilities: From the Basics of Recognition to Inhibition of Transcription Factor-DNA Complexes Paul Langan Neutron technologies for nucleic acid research and drug design and delivery 10:00 10:30 Speaker Group Photo Time and Coffee Break Chair: David Lynn 10:30 11:00 11:00 11:30 11:30 12:00 Andrzej Joachimiak Structure Determination of transcriptional factors and their complexes with DNA Ichiro Hirao Expansion of the genetic alphabet of DNA and its application to aptamer generation Irene Weber HIV Protease: the Challenge of Drug Resistance 12:00 13:00 Sandwich Lunch and Poster Session Chair: Martin Egli 13:00 13:30 13:30 14:00 14:00 14:30 14:30 15:00 Bi-Cheng Wang Exploring the Biophysical/Biochemical Information of Metals in Macromolecules Using Wavelength-Dependent Data Eric Ennifar Thermodynamics of HIV-1 Reverse Transcriptase in action reveals the mechanism of action of non-nucleoside inhibitors Margo A. Brinton Viral 3 RNA structures interacting with cell proteins regulate the initiation of flavivirus RNA synthesis Robert T. Batey Recognition of cobalamins by riboswitches

7 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY 5 15:00 15:30 Coffee Break Chair: Markus Germann 15:30 16:00 16:00 16:30 16:30 17:00 Jeffrey Kieft Molecular self-defense: viral RNAs that use structure to inhibit host cell nucleases Martin Egli Structure, Kinetics and Mechanism of 8-oxoG Bypass by Y-Class DNA Polymerases Zhen Huang Chemistry and Structural Biology of Nucleic Acids Functionalized with Selenium 17:00 21:00 Speakers Dinner Banquet and Social Hour Sunday, Sep. 15, 2013 Chair: Loren Williams 7:30 8:00 am Registration & Continental Breakfast 8:00 8:30 8:30 9:00 9:00 9:30 9:30 10:00 David Lynn Designing Chimeric Biomolecule Self-Assemblies Gaohua Liu Applications of Protein NMR in Protein Engineering and Design Suresh Srivastava RNA Synthesis in Reverse Direction and Application in Convenient Introduction of Ligands, Chromophores and Modifications of Synthetic RNA at the 3 - End and Highly Efficient Synthesis of Long RNA Li-Wei Hung Automated Crystallographic Structure Determination in PHENIX 10:00 10:20 Coffee Break Chair: Eric Ennifar 10:20 10:50 10:50 11:10 11:10 11:40 11:40 12:00 Loren Williams RNA and Protein - a match made in the Hadean Wen Zhang Facilitation of DNA Crystallization by Selenium Functionalization Markus W. Germann Structural and Dynamic Aspects of DNA Recognition Bo Xiao Mannosylated bioreducible nanoparticle-mediated macrophage-specific TNF-α RNA interference for IBD therapy 12:00 13:30 Box Lunch, Poster Session, Poster Award Announcement, and Closing

8 6 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY Understanding the Structural Basis of the Function of Various Factors in the Steps of Protein Synthesis Thomas A. Steitz, Yury Polikanov, Matthieu Gagnon, Sai Seetharaman, Jinzhong Lin, Ivan Lomakin Department of Molecular Biophysics & Biochemistry and Department of Chemistry, Yale University, and Howard Hughes Medical Institute, New Haven, Connecticut USA; We have obtained many insights into the structural basis of ribosome function in protein synthesis from our structural studies of the large ribosomal subunit as well as the 70S bacterial ribosome, and their complexes with substrates, protein factors or antibiotics. These have elucidated the mechanism by which this ribozyme catalyzes peptide bond formation and the specificity and mode of its inhibition by antibiotics. During the process of protein synthesis elongation, the 70S ribosome is in various conformational states bound to various different ligands, and the structures of these functional states are beginning to emerge. Our structure of the 70S ribosome complexed with an mrna, trna fmet in the P site and elongation factor P (EF-P), shows EF-P bound between the P site and the E site and interacting extensively with the P-site trna along its entire length. However, how EF-P facilitates the translation through short runs of proline is as yet unknown. Our most recent structures of the 70S ribosome bound to either hibernation promoting factor or ribosome modulation factor show how these factors prevent the initiation of protein synthesis by blocking trna binding or interaction with the Shine-Dalgarno mrna sequences. We have also obtained the structure of a complex with a ribosome rescue protein (yaej), which rescues stalled ribosomes by hydrolyzing the peptidyl-trna. It binds to the site used by the release factors, but is positioned by a peptide tail that lies in the mrna binding cleft. Protein synthesis by the ribosome can be regulated by numerous different nascent chain sequences and the binding of a small molecule ligand, resulting in polypeptide chain arrest. Progress has been made in obtaining a crystal structure of the 70S ribosome containing an ermc arrested peptidyl-trna in the tunnel along with erythromycin. Recently, interesting progress has been made on understanding the structural basis of the function of initiation factors eif1 and eif1a from low resolution structures of eukaryotic 40S subunit complexes with these factors as well as trna and mrna.

9 THE 3RD INTERNATIONAL CONFERENCE ON NUCLEIC ACID-PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY FOR DRUG DISCOVERY 7 Thomas A. Steitz Department of Molecular Biophysics and Biochemistry, Yale University, and Howard Hughes Medical Institute, New Haven, CT Thomas A. Steitz is Sterling Professor of Molecular Biophysics and Biochemistry and Professor of Chemistry at Yale University as well as an Investigator of the Howard Hughes Medical Institute. He received a B.A. degree in chemistry from Lawrence University and a Ph.D. degree in molecular biology and biochemistry from Harvard. After postdoctoral research at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England he joined the Yale faculty. He is a member of the U.S. National Academy of Sciences, the American Academy of Arts and Sciences and a Foreign Member of the Royal Society. He has received a number of awards, including the Rosenstiel Award for distinguished work in basic biomedical sciences, the Keio Medical Science Prize, the Gairdner International Award, the Connecticut Medal of Science and the 2009 Nobel Prize in Chemistry. For the last three decades, research in the laboratory of Dr. Steitz has focused on obtaining insights into the molecular mechanisms by which the proteins and nucleic acids involved in the central dogma of molecular biology carry out gene expression from replication and recombination of the DNA genome to its transcription into mrna followed by the various components associated with the translation of mrna into protein. Not only are these processes fundamental to all life forms, but many of the macromolecules involved in these processes are known, or potential, targets for therapeutic drugs. In the 1980s, his lab established the structure of the catabolite gene activator protein and later its DNA complex, the structure of the first DNA polymerase and the first structure of an aminoacyl trna synthetase bound to trna. His lab is now continuing structural studies of all the components of the replisome. His studies of T7 RNA polymerase captured in many of its functionally important states - initiation, intermediate, elongation - as well as stages of nucleotide incorporation and provide the most complete picture of RNA transcription by an RNA polymerase. Perhaps the most significant insights have been derived from the atomic structure of the large ribosomal subunit. This structure proved that the ribosomal RNA is entirely responsible for catalyzing peptide bond formation and provided insights into how this mammoth RNA assembly is folded and functions as an enzyme. Most recently, research has focused on the structures of the 70S ribosome in complex with factors involved in various steps of the protein synthesis process. The ribosome is probably the major target of antibiotics. The many structures of the large subunit complexed with various different antibiotics determined at Yale have identified numerous different antibiotic binding sites near the site of protein synthesis. This information has been enormously facilitating to Rib-X Pharmaceuticals, Inc. in the development of new antibiotics effective against the antibiotic resistant bacteria.