April, 2008: 15 (4)
"Solvent Structure and Ribozyme Catalysis"
[Cover Caption]
Browse Archive
 In This Issue | Pages |
|---|---|
| In This Issue | ix |
| Innovations | Pages |
| Regeneron Focuses on Age-Related Macular Degeneration Wendy Wolfson | 303 |
| Previews | Pages |
| PAK'n It In: Identification of a Selective PAK Inhibitor Gary M. Bokoch | 305 |
| Sweetly Expanding Enzymatic Glycodiversification David L. Jakeman | 307 |
| The Tail of Mycolic Acids Jeff Zhiqiang Lu and Sean T. Prigge | 309 |
| Studying Posttranslational Modifications by In-Cell NMR G. Lippens, I. Landrieu, and X. Hanoulle | 311 |
| Articles | Pages |
| Ethylene Receptor Antagonists: Strained Alkenes Are Necessary but Not Sufficient Michael C. Pirrung, Anthony B. Bleecker, Yoshihisa Inoue, Fernando I. Rodríguez, Norimitsu Sugawara, Takehiko Wada, Yunfan Zou, and Brad M. Binder | 313 |
| An Isoform-Selective, Small-Molecule Inhibitor Targets the Autoregulatory Mechanism of p21-Activated Kinase Sean W. Deacon, Alexander Beeser, Jami A. Fukui, Ulrike E.E. Rennefahrt, Cynthia Myers, Jonathan Chernoff, and Jeffrey R. Peterson | 322 |
| Solvent Structure and Hammerhead Ribozyme Catalysis Monika Martick, Tai-Sung Lee, Darrin M. York, and William G. Scott | 332 |
| Toward Deciphering the Code to Aminergic G Protein-Coupled Receptor Drug Design Edwin S. Tan, Eli S. Groban, Matthew P. Jacobson, and Thomas S. Scanlan | 343 |
| Structure-Activity Relationships of Antibacterial Acyl-Lysine Oligomers Inna S. Radzishevsky, Tchelet Kovachi, Yaara Porat, Lior Ziserman, Fadia Zaknoon, Dganit Danino, and Amram Mor | 354 |
| PAP Inhibitor with In Vivo Efficacy Identified by Candida albicans Genetic Profiling of Natural Products Bo Jiang, Deming Xu, John Allocco, Craig Parish, John Davison, Karynn Veillette, Susan Sillaots, Wenqi Hu, Roberto Rodriguez-Suarez, Steve Trosok, Li Zhang, Yang Li, Fariba Rahkhoodaee, Tara Ransom, Nick Martel, Hao Wang, Daniel Gauvin, Judyann Wiltsie, Douglas Wisniewski, Scott Salowe, Jennifer Nielsen Kahn, Ming-Jo Hsu, Robert Giacobbe, George Abruzzo, Amy Flattery, Charles Gill, Phil Youngman, Ken Wilson, Gerald Bills, Gonzalo Platas, Fernando Pelaez, Maria Teresa Diez, Sarah Kauffman, Jeff Becker, Guy Harris, Paul Liberator, and Terry Roemer | 363 |
| Mitochondria-Penetrating Peptides Kristin L. Horton, Kelly M. Stewart, Sonali B. Fonseca, Qian Guo, and Shana O. Kelley | 375 |
| Structure-Based Design of a Superagonist Ligand for the Vitamin D Nuclear Receptor Shinji Hourai, Luis Cezar Rodrigues, Pierre Antony, Bernardo Reina-San-Martin, Fabrice Ciesielski, Benjamin Claude Magnier, Kristina Schoonjans, Antonio Mouriño, Natacha Rochel, and Dino Moras | 383 |
| Optimizing Glycosyltransferase Specificity via “Hot Spot” Saturation Mutagenesis Presents a Catalyst for Novobiocin Glycorandomization Gavin J. Williams, Randal D. Goff, Changsheng Zhang, and Jon S. Thorson | 393 |
| Separate Entrance and Exit Portals for Ligand Traffic in Mycobacterium tuberculosis FabH Sarbjot Sachdeva, Faik N. Musayev, Mamoun M. Alhamadsheh, J. Neel Scarsdale, H. Tonie Wright, and Kevin A. Reynolds | 402 |
Cover Caption
On the cover: Ribbon diagram of full-length hammerhead ribozyme, as determined from the 2.2 Å crystal structure. The substrate strand is light-blue and the enzyme strand is dark blue. The general base in the active site, G12, is red, and the general acid, G8, is magenta. The cleavage-site nucleotide, C17, is white, as is the adjacent A1.1, the leaving group in the cleavage reaction. Manganese ions are depicted as small purple spheres. The figure was created with PyMOL. See Martick et al., pp. 332–342.
Featured Article
- PAP Inhibitor with In Vivo Efficacy Identified by Candida albicans Genetic Profiling of Natural Products
Bo Jiang, Deming Xu, John Allocco, Craig Parish, John Davison, Karynn Veillette, Susan Sillaots, Wenqi Hu, Roberto Rodriguez-Suarez, Steve Trosok, Li Zhang, Yang Li, Fariba Rahkhoodaee, Tara Ransom, Nick Martel, Hao Wang, Daniel Gauvin, Judyann Wiltsie, Douglas Wisniewski, Scott Salowe, Jennifer Nielsen Kahn, Ming-Jo Hsu, Robert Giacobbe, George Abruzzo, Amy Flattery, Charles Gill, Phil Youngman, Ken Wilson, Gerald Bills, Gonzalo Platas, Fernando Pelaez, Maria Teresa Diez, Sarah Kauffman, Jeff Becker, Guy Harris, Paul Liberator, and Terry Roemer
[Summary] [Full Text] [PDF] [Supplemental Data] - Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.
