Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-Like Proteins Support a Highly Dynamic Domain Architecture [Protein Structure and Folding]

September 5th, 2016 by Miller, B. R., Drake, E. J., Shi, C., Aldrich, C. C., Gulick, A. M.

Nonribosomal peptide synthetases (NRPSs) produce a wide variety of peptide natural products. During synthesis, the multidomain NRPSs act as an assembly line, passing the growing product from one module to the next. Each module generally consists of an integrated peptidyl carrier protein (PCP), an amino acid-loading adenylation domain, and a condensation domain that catalyzes peptide bond formation. Some adenylation domains interact with small partner proteins called MbtH-like proteins (MLPs) that enhance solubility or activity. A structure of an MLP bound to an adenylation domain has been previously reported using a truncated adenylation domain, precluding any insight that might derive from understanding the influence of the MLP on the intact adenylation domain or on the dynamics of the entire NRPS module. Here, we present the structures of the full length NRPS EntF bound to the MLPs from E. coli and Pseudomonas aeruginosa. These new structures, along with biochemical and bioinformatic support, further elaborate the residues that define the MLP-adenylation domain interface. Additionally the structures highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.
  • Posted in Journal of Biological Chemistry, Publications
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Overcoming resistance to HER2 inhibitors through state-specific kinase binding

September 5th, 2016 by Chris J Novotny

Nature Chemical Biology 12, 923 (2016). doi:10.1038/nchembio.2171

Authors: Chris J Novotny, Sirkku Pollari, Jin H Park, Mark A Lemmon, Weijun Shen & Kevan M Shokat

  • Posted in Nat Chem Biol, Publications
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Small-molecule WNK inhibition regulates cardiovascular and renal function

September 5th, 2016 by Ken Yamada

Nature Chemical Biology 12, 896 (2016). doi:10.1038/nchembio.2168

Authors: Ken Yamada, Hyi-Man Park, Dean F Rigel, Keith DiPetrillo, Erin J Whalen, Anthony Anisowicz, Michael Beil, James Berstler, Cara Emily Brocklehurst, Debra A Burdick, Shari L Caplan, Michael P Capparelli, Guanjing Chen, Wei Chen, Bethany Dale, Lin Deng, Fumin Fu, Norio Hamamatsu, Kouki Harasaki, Tracey Herr, Peter Hoffmann, Qi-Ying Hu, Waan-Jeng Huang, Neeraja Idamakanti, Hidetomo Imase, Yuki Iwaki, Monish Jain, Jey Jeyaseelan, Mitsunori Kato, Virendar K Kaushik, Darcy Kohls, Vidya Kunjathoor, Daniel LaSala, Jongchan Lee, Jing Liu, Yang Luo, Fupeng Ma, Ruowei Mo, Sarah Mowbray, Muneto Mogi, Flavio Ossola, Pramod Pandey, Sejal J Patel, Swetha Raghavan, Bahaa Salem, Yuka H Shanado, Gary M Trakshel, Gordon Turner, Hiromichi Wakai, Chunhua Wang, Stephen Weldon, Jennifer B Wielicki, Xiaoling Xie, Lingfei Xu, Yukiko I Yagi, Kayo Yasoshima, Jianning Yin, David Yowe, Ji-Hu Zhang, Gang Zheng & Lauren Monovich

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

  • Posted in Nat Chem Biol, Publications
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Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

September 5th, 2016 by Gizem Akçay

Nature Chemical Biology 12, 931 (2016). doi:10.1038/nchembio.2174

Authors: Gizem Akçay, Matthew A Belmonte, Brian Aquila, Claudio Chuaqui, Alexander W Hird, Michelle L Lamb, Philip B Rawlins, Nancy Su, Sharon Tentarelli, Neil P Grimster & Qibin Su

  • Posted in Nat Chem Biol, Publications
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Simultaneous analysis of enzyme structure and activity by kinetic capillary electrophoresis–MS

September 5th, 2016 by Gleb G Mironov

Nature Chemical Biology 12, 918 (2016). doi:10.1038/nchembio.2170

Authors: Gleb G Mironov, Christopher M Clouthier, Abdullah Akbar, Jeffrey W Keillor & Maxim V Berezovski

  • Posted in Nat Chem Biol, Publications
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YidC assists the stepwise and stochastic folding of membrane proteins

September 5th, 2016 by Tetiana Serdiuk

Nature Chemical Biology 12, 911 (2016). doi:10.1038/nchembio.2169

Authors: Tetiana Serdiuk, Dhandayuthapani Balasubramaniam, Junichi Sugihara, Stefania A Mari, H Ronald Kaback & Daniel J Müller

  • Posted in Nat Chem Biol, Publications
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Summer 2016 newsletter released

August 31st, 2016 by pthomas2

Welcome back from the ACS meeting in Philadelphia! The summer newsletter was just released. BIOL members should have received it in their email. You can find the newsletter here.

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

August 29th, 2016 by Tinghu Zhang

Nature Chemical Biology 12, 876 (2016). doi:10.1038/nchembio.2166

Authors: Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E Dixon-Clarke, Brian J Abraham, Ann K Greifenberg, Scott B Ficarro, Jonathan M Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L Greenleaf, Jarrod A Marto, Matthias Geyer, Alex N Bullock, Richard A Young & Nathanael S Gray

  • Posted in Nat Chem Biol, Publications
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Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

August 29th, 2016 by Tanvi Shekhar-Guturja

Nature Chemical Biology 12, 867 (2016). doi:10.1038/nchembio.2165

Authors: Tanvi Shekhar-Guturja, G M Kamal B Gunaherath, E M Kithsiri Wijeratne, Jean-Philippe Lambert, Anna F Averette, Soo Chan Lee, Taeyup Kim, Yong-Sun Bahn, Farida Tripodi, Ron Ammar, Katja Döhl, Karolina Niewola-Staszkowska, Lutz Schmitt, Robbie J Loewith, Frederick P Roth, Dominique Sanglard, David Andes, Corey Nislow, Paola Coccetti, Anne-Claude Gingras, Joseph Heitman, A A Leslie Gunatilaka & Leah E Cowen

  • Posted in Nat Chem Biol, Publications
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Genetic code expansion in the mouse brain

August 29th, 2016 by Russell J Ernst

Nature Chemical Biology 12, 776 (2016). doi:10.1038/nchembio.2160

Authors: Russell J Ernst, Toke P Krogager, Elizabeth S Maywood, Roberto Zanchi, Václav Beránek, Thomas S Elliott, Nicholas P Barry, Michael H Hastings & Jason W Chin

Site-specific incorporation of non-natural amino acids into proteins, via genetic code expansion with pyrrolysyl tRNA synthetase (PylRS) and tRNAPylCUA pairs (and their evolved derivatives) from Methanosarcina sp., forms the basis of powerful approaches to probe and control protein function in cells and invertebrate organisms. Here we demonstrate that adeno-associated viral delivery of these pairs enables efficient genetic code expansion in primary neuronal culture, organotypic brain slices and the brains of live mice.