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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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.

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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

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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.

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

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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

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Leptin Enhances TH2 and ILC2 Responses in Allergic Airway Disease [Molecular Bases of Disease]

August 26th, 2016 by Zheng, H., Zhang, X., Castillo, E. F., Luo, Y., Liu, M., Yang, X. O.

Allergic asthma and obesity are the leading health problems in the world. Many studies have shown that obesity is a risk factor of development of asthma. However, the underlying mechanism has not been well established. In this study, we demonstrate that leptin, an adipokine elevated in obese individuals, promoted proliferation and survival of pro-allergic type 2 helper T cells and group 2 innate lymphoid cells and production of type 2 cytokines, which together contribute to allergic responses. Leptin activates mTORC1, MAPK and STAT3 pathways in TH2 cells. The effects of leptin on TH2 cell proliferation, survival and cytokine production are dependent on the mTORC1 and MAPK pathways as revealed by specific inhibitors. In vivo, leptin-deficiency led to attenuated experimental allergic airway inflammation. Our results thus support that obesity associated elevation of leptin may increase the susceptibility of asthma via modulation of pro-allergic lymphocyte responses.

Proof of Principle: Coronin 1A – An Intrinsic Modulator of T Lymphocyte Function [Signal Transduction]

August 26th, 2016 by Siegmund, K., Klepsch, V., Hermann-Kleiter, N., Baier, G.

Coronins are evolutionarily conserved proteins that were originally identified as modulators of actin-dependent processes. Studies analyzing complete Coronin 1a knockout mice have shown that this molecule is an important regulator of T cell homeostasis and it has been linked to immune deficiencies as well as autoimmune disorders. Nevertheless, since Coronin 1A is strongly expressed in all leukocyte subsets, it is not conclusive whether or not this phenotype is attributed to a T cell-intrinsic function of Coronin 1A. To address this research question, we have generated a T cell-specific Coronin 1a knockout mouse (Coro1afl/fl x Cd4[Cre]). Deletion of Coro1a specifically in T cells led to a strong reduction in T cell number and a shift towards the effector/memory phenotype in peripheral lymphoid organs when compared to Cd4[Cre] mice expressing wild-type Coro1a. In contrast to peripheral lymphoid tissue, thymocyte number and subsets were not affected by the deletion of Coro1a. Furthermore, T cell-specific Coro1a knockout mice were largely resistant to the induction of autoimmunity when tested in the MOG-induced EAE mouse model of multiple sclerosis. Thus, the phenotype of T cell-specific Coro1a deletion resembles the phenotype observed with conventional (whole body) Coro1a knockout mice. In summary, our findings provide formal proof of the predominant T cell-intrinsic role of Coronin 1A.

Nuclear Magnetic Resonance Observation of α-Synuclein Membrane Interaction by Monitoring the Acetylation Reactivity of Its Lysine Side Chains

August 23rd, 2016 by Jung Ho Lee, Jinfa Ying and Ad Bax

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Biochemistry
DOI: 10.1021/acs.biochem.6b00637

Apolipoprotein C-III Nanodiscs Studied by Site-Specific Tryptophan Fluorescence

August 23rd, 2016 by Chase A. Brisbois and Jennifer C. Lee

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Biochemistry
DOI: 10.1021/acs.biochem.6b00599