Sigel, Dawn M
Sigel, Dawn M. of cofactor-specific, bactericidalMycobacterium tuberculosisInhA inhibitors using DNA-encoded library technology == Holly H. Soutter, Paolo Centrella, Matthew A. Clark, John W. Cuozzo, Christoph E. Dumelin, Marie-Aude Guie, Sevan Emiglitate Habeshian, Anthony Deb. Keefe, Kaitlyn M. Kennedy, Eric A. Sigel, Dawn M. Troast, Ying Zhang, Andrew Deb. Ferguson, Gareth Davies, Eleanor R. Stead, Jason Breed, Prashanti Madhavapeddi, and Jon A. Read The increasing prevalence of multidrug-resistant strains of tuberculosis has created an urgent need for book therapies to treat tuberculosis infections. Here we have demonstrated the successful utilization of the DNA-encoded X-Chem technology for the discovery inhibitors ofMycobacterium tuberculosisenoylacyl-carrier protein (ACP) reductase, InhA, a validated target to get the treatment of tuberculosis. The determined inhibitors are cofactor specific and have activity in multiple cellular assays. Crystal structures of consultant compounds from five chemical series revealed that the compounds bind adjacent to the NADH cofactor and adopt a variety of conformations, including two previously unreported binding modes. The compounds determined may serve as useful qualified prospects in the development of new antibacterial drugs with efficacy against multidrug-resistant tuberculosis. (See pp. E7880E7889. ) == Substrate recognition and catalysis by GH47 -mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway == Yong Xiang, Khanita Karaveg, and Kelley W. Moremen Asn-linked glycosylation of newly synthesized polypeptides happens in the endoplasmic reticulum of eukaryotic cells. Glycan structures are trimmed and remodeled as they transit the secretory pathway, and processing intermediates play various roles because ligands to get folding chaperones and signals for quality control and intracellular transport. Key methods for the generation of those trimmed intermediates are catalyzed by glycoside hydrolase family members 47 (GH47) -mannosidases that selectively cleave 1, 2-linked mannose residues. Despite the series and structural similarities among the GH47 enzymes, the molecular basis to get residue-specific cleavage remains obscure. The present studies reveal enzymesubstrate complex structures for two related GH47 -mannosidases and provide insights into how these enzymes recognize the same substrates differently and catalyze the complementary glycan trimming reactions necessary for glycan maturation. (See pp. E7890E7899. ) == Molecular evidence of keratin and melanosomes in feathers of the Early Cretaceous birdEoconfuciusornis == Yanhong Pan, Wenxia Zheng, Alison E. Moyer, Jingmai K. OConnor, Min Wang, Xiaoting Zheng, Xiaoli Wang, Elena R. Schroeter, Zhonghe Zhou, and Mary H. Schweitzer We report fossil evidence of feather structural protein (beta-keratin) from a 130-My-old basal bird (Eoconfuciusornis) from the popular Early Cretaceous Jehol Biota, which has produced many feathered dinosaurs, early birds, and mammals. Multiple independent molecular analyses of both microbodies and associated matrix recovered from the fossil feathers confirm that these microbodies are indeed melanosomes. We use transmission electron microscopy and immunogold to show localized binding of antibodies raised against feather protein to matrix filaments within these ancient feathers. Our work sheds new light on molecular constituents of tissues preserved in fossils. (See pp. E7900E7907. ) == Paired quantitative and qualitative evaluation of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA == Julio C. C. Lorenzi, Emiglitate Yehuda Z. Cohen, Lillian W. Cohn, Edward F. Kreider, John P. Barton, Gerald H. Learn, Thiago Oliveira, Christy L. Lavine, Joshua A. Horwitz, Allison Settler, Mila Jankovic, Michael H. Seaman, Arup K. Chakraborty, Beatrice H. Hahn, Flotta Caskey, and Michel C. Nussenzweig A reservoir of latently Emiglitate infected cells positions the greatest challenge to HIV-1 eradication. Attempts to develop strategies Rabbit Polyclonal to MGST1 to eliminate the reservoir have been hampered, in part, by the lack of a precise understanding of the cellular and molecular character of this reservoir. We describe a new solution to analyze the replication-competent latent reservoir quantitatively and qualitatively..