A prevalent intraresidue hydrogen bond stabilizes proteins

October 17th, 2016 by Robert W Newberry

Nature Chemical Biology 12, 1084 (2016). doi:10.1038/nchembio.2206

Authors: Robert W Newberry & Ronald T Raines

Identification and characterization of PPARα ligands in the hippocampus

October 17th, 2016 by Avik Roy

Nature Chemical Biology 12, 1075 (2016). doi:10.1038/nchembio.2204

Authors: Avik Roy, Madhuchhanda Kundu, Malabendu Jana, Rama K Mishra, Yeni Yung, Chi-Hao Luan, Frank J Gonzalez & Kalipada Pahan

  • Posted in Nat Chem Biol, Publications
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Discovery of MRSA active antibiotics using primary sequence from the human microbiome

October 17th, 2016 by John Chu

Nature Chemical Biology 12, 1004 (2016). doi:10.1038/nchembio.2207

Authors: John Chu, Xavier Vila-Farres, Daigo Inoyama, Melinda Ternei, Louis J Cohen, Emma A Gordon, Boojala Vijay B Reddy, Zachary Charlop-Powers, Henry A Zebroski, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Steven Park, David S Perlin, Joel S Freundlich & Sean F Brady

Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.

  • Posted in Nat Chem Biol, Publications
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Structural basis of nonribosomal peptide macrocyclization in fungi

October 17th, 2016 by Jinru Zhang

Nature Chemical Biology 12, 1001 (2016). doi:10.1038/nchembio.2202

Authors: Jinru Zhang, Nicholas Liu, Ralph A Cacho, Zhou Gong, Zhu Liu, Wenming Qin, Chun Tang, Yi Tang & Jiahai Zhou

Nonribosomal peptide synthetases (NRPSs) in fungi biosynthesize important pharmaceutical compounds, including penicillin, cyclosporine and echinocandin. To understand the fungal strategy of forging the macrocyclic peptide linkage, we determined the crystal structures of the terminal condensation-like (CT) domain and the holo thiolation (T)-CT complex of Penicillium aethiopicum TqaA. The first, to our knowledge, structural depiction of the terminal module in a fungal NRPS provides a molecular blueprint for generating new macrocyclic peptide natural products.

Mn4Ca Cluster of Photosynthetic Oxygen-Evolving Center: Structure, Function and Evolution

October 14th, 2016 by James Barber

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.6b00794

ACS 253rd National Meeting News

October 14th, 2016 by Šileikyte, J., Blachly–Dyson, E., Sewell, R., Carpi, A., Menabo, R., Di Lisa, F., Ricchelli, F., Bernardi, P., Forte, M.

  1. Abstract deadline Oct. 31, 2016 for Spring 2017 meeting in San Francisco

In addition to poster sessions, there will be oral sessions for contributed papers from Graduate students and postdocs, Early Career Investigators and (New!) Mid Career investigators.

Abstract submissions at https://callforpapers.acs.org/sanfran2017/BIOL

  1. Travel Award deadline Jan. 15, 2017 for the Spring 2017 meeting.

Application and information at http://www.divbiolchem.org/awards/travel-awards/

  1. (New!) Symposium proposals for Spring 2018 meeting deadline Feb. 15, 2017

We are soliciting proposals for symposia for the 2018 meetings.  Download the application here.

  1. Spring 2017 Program Preview
  • Ronald Breslow Award for Achievement in Biomimetic Chemistry: Symposium in honor of Benjamin G. Davis
  • ACS Award in Pure Chemistry: Symposium in honor of Neal K. Devaraj
  • Goodman Award: Symposium in honor of Jennifer Doudna
  • ACS Chemical Biology Award Symposium (organizer L. Kiessling)
  • Nucleic Acid Therapeutics: mechanisms  and applications (organizer M. Manoharan)
  • Self-assembly of small molecules in the cellular milieu (organizer B. Xu)
  • Metalloprotein-initiated Signaling Transduction Response to Redox Stress (organizer A. Liu)
  • Chemical Probes for Bacterial Imaging (organizer E. Carlson)
  • Chemical Epigenetics (organizer D. Fujimori)

Crotonic Acid Blocks the Gloeobacter Ligand-Gated Ion Channel (GLIC) via the Extracellular Domain

October 14th, 2016 by Mona A. Alqazzaz, Kerry L. Price and Sarah C. R. Lummis

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.6b00531

The phosphoinositide 3-kinase regulates retrograde trafficking of the iron permease CgFtr1 and iron homeostasis in Candida glabrata [Microbiology]

October 11th, 2016 by Sharma, V., Purushotham, R., Kaur, R.

The phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol and produces PI3P, has been implicated in protein trafficking, intracellular survival and virulence in the pathogenic yeast Candida glabrata. Here, we demonstrate PI3-kinase (CgVps34) to be essential for maintenance of cellular iron homeostasis. We examine how CgVps34 regulates the fundamental process of iron acquisition, and underscore its function in vesicular trafficking as a central determinant. RNA-sequencing analysis revealed iron homeostasis genes to be differentially expressed upon CgVps34 disruption. Consistently, the Cgvps34Δ mutant displayed growth attenuation in low- and high-iron media, increased intracellular iron content, elevated mitochondrial aconitase activity, impaired biofilm formation and extenuated mouse organ colonization potential. Further, we demonstrate for the first time that C. glabrata cells respond to iron-limitation by expressing the iron permease CgFtr1 primarily on the cell membrane, and to iron-excess via internalization of the plasma membrane-localized CgFtr1 to the vacuole. Our data show that CgVps34 is essential for the latter process. We also report that macrophage-internalized C. glabrata cells express CgFtr1 on the cell membrane indicative of an iron-restricted macrophage internal milieu, and Cgvps34Δ cells display better survival in iron-enriched medium-cultured macrophages. Overall, our data reveal the centrality of PI3K signaling in iron metabolism and host colonization.
  • Posted in Journal of Biological Chemistry, Publications
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Cdc24 is essential for long-range end resection in the repair of dsDNA breaks [Metabolism]

October 11th, 2016 by Zhang, H., Hua, Y., Li, R., Kong, D.

Double-stranded DNA breaks (DSBs) are highly detrimental DNA lesions, which may be repaired by the homologous recombination-mediated repair pathway. The 5 prime to 3 prime direction of long-range end resection on one DNA strand, in which 3 prime-single-strand DNA overhangs are created from broken DNA ends, is an essential step in this pathway. Dna2 has been demonstrated as an essential nuclease in this event, but the molecular mechanism how Dna2 is recruited to DNA break sites in vivo is not elucidated. In this study, a novel recombination factor called Cdc24 was identified in fission yeast. We demonstrated that Cdc24 localizes to DNA break sites during the repair of DNA breaks and is an essential factor for long-range end resection. We also determined that Cdc24 plays a direct role in recruiting Dna2 to DNA break sites through its interaction with Dna2 and replication protein A (RPA). Further, this study revealed that RPA acts as a foundation in assembling the machinery for long-range end resection by its essential role in recruiting Cdc24 and Dna2 to DNA break sites. These results define Cdc24 as an essential factor for long-range end resection in the repair of DSBs, opening the door for further investigations into the enzymes involved in long-range end resection for DSB repair.

Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection

October 10th, 2016 by Gahl Levy

Nature Chemical Biology 12, 1037 (2016). doi:10.1038/nchembio.2193

Authors: Gahl Levy, Naomi Habib, Maria Angela Guzzardi, Daniel Kitsberg, David Bomze, Elishai Ezra, Basak E Uygun, Korkut Uygun, Martin Trippler, Joerg F Schlaak, Oren Shibolet, Ella H Sklan, Merav Cohen, Joerg Timm, Nir Friedman & Yaakov Nahmias

  • Posted in Nat Chem Biol, Publications
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