Computational design of ligand-binding membrane receptors with high selectivity

May 1st, 2017 by Xiang Feng

Nature Chemical Biology 13, 715 (2017). doi:10.1038/nchembio.2371

Authors: Xiang Feng, Joaquin Ambia, Kuang-Yui M Chen, Melvin Young & Patrick Barth

  • Posted in Nat Chem Biol, Publications
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Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

May 1st, 2017 by Linda Lauinger

Nature Chemical Biology 13, 709 (2017). doi:10.1038/nchembio.2370

Authors: Linda Lauinger, Jing Li, Anton Shostak, Ibrahim Avi Cemel, Nati Ha, Yaru Zhang, Philipp E Merkl, Simon Obermeyer, Nicolas Stankovic-Valentin, Tobias Schafmeier, Walter J Wever, Albert A Bowers, Kyle P Carter, Amy E Palmer, Herbert Tschochner, Frauke Melchior, Raymond J Deshaies, Michael Brunner & Axel Diernfellner

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Reactive Oxygen Species Production Induced by Pore Opening in Cardiac Mitochondria: The Role of Complex II [Bioenergetics]

April 27th, 2017 by Paavo Korge, Scott A John, Guillaume Calmettes, James N Weiss

Succinate-driven reverse electron transport (RET) through complex I is hypothesized be a major source of ROS that induce permeability transition pore (PTP) opening and damage the heart during ischemia/reperfusion. Since RET can only generate ROS when mitochondria are fully polarized, however, this mechanism is self-limiting once PTP open during reperfusion. In the companion manuscript, we showed that ROS production after PTP opening can be sustained when complex III is damaged (simulated by antimycin). Here we show that complex II can also contribute to sustained ROS production in isolated rabbit cardiac mitochondria following inner membrane pore formation induced by either alamethicin or Ca-induced PTP opening. Two conditions are required to maximize malonate-sensitive ROS production by complex II in isolated mitochondria: a) complex II inhibition by atpenin A5 or complex III inhibition by stigmatellin that results in succinate-dependent reduction of the dicarboxylate binding site of complex II (site IIf ); b) pore opening in the inner membrane resulting in rapid efflux of succinate/fumarate and other dicarboxylates capable of competitively binding to site IIf. The decrease in matrix [dicarboxylates] allows O2 access to reduced site IIf, thereby making electron donation to O2 possible, explaining the rapid increase in ROS production provided that site IIf is reduced. Because ischemia is known to inhibit complexes II and III and increase matrix succinate/fumarate levels, we hypothesize that by allowing dicarboxylate efflux from the matrix, PTP opening during reperfusion may activate sustained ROS production by this mechanism after RET-driven ROS production has ceased.

Protein degradation: DCAFinating splicing

April 24th, 2017 by Georg E Winter

Nature Chemical Biology 13, 575 (2017). doi:10.1038/nchembio.2378

Author: Georg E Winter

Chemical control of protein homeostasis and induction of protein destabilization are emerging therapeutic strategies. Two recent studies identify a set of sulfonamides that can modulate the CRL4DCAF15 E3 ligase complex to target the splicing factor RBM39 for proteasomal degradation.

Global survey of the immunomodulatory potential of common drugs

April 24th, 2017 by Gregory I Vladimer

Nature Chemical Biology 13, 681 (2017). doi:10.1038/nchembio.2360

Authors: Gregory I Vladimer, Berend Snijder, Nikolaus Krall, Johannes W Bigenzahn, Kilian V M Huber, Charles-Hugues Lardeau, Kumar Sanjiv, Anna Ringler, Ulrika Warpman Berglund, Monika Sabler, Oscar Lopez de la Fuente, Paul Knöbl, Stefan Kubicek, Thomas Helleday, Ulrich Jäger & Giulio Superti-Furga

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

April 24th, 2017 by Taisuke Uehara

Nature Chemical Biology 13, 675 (2017). doi:10.1038/nchembio.2363

Authors: Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka & Takashi Owa

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Immunology: Mind the immuno-connection gap

April 24th, 2017 by Wolfgang Link

Nature Chemical Biology 13, 572 (2017). doi:10.1038/nchembio.2373

Author: Wolfgang Link

Biologic drugs that modulate the immune system have revolutionized the therapeutic landscape for several selected cancer types. A new study reports an image-based assay system to monitor cell–cell interactions, identifying small-molecule compounds with immunomodulatory capacity.

Redox-Sensitive MarR Homologue BifR from Burkholderia thailandensis Regulates Biofilm Formation

April 21st, 2017 by Ashish Gupta, Stanley M. Fuentes and Anne Grove

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.7b00103

Two Distinct Assembly States of the Cysteine Regulatory Complex of Salmonella typhimurium Are Regulated by Enzyme–Substrate Cognate Pairs

April 21st, 2017 by Abhishek Kaushik, Mary Krishna Ekka and Sangaralingam Kumaran

TOC Graphic

Biochemistry
DOI: 10.1021/acs.biochem.6b01204

Disease-Associated Extracellular Loop Mutations in the Adhesion G Protein-Coupled Receptor G1 (ADGRG1; GPR56) Differentially Regulate Downstream Signaling [Molecular Bases of Disease]

April 19th, 2017 by Ayush Kishore, Randy A. Hall

Mutations to the adhesion G protein-coupled receptor ADGRG1 (G1; also known as GPR56) underlie the neurological disorder bilateral frontoparietal polymicrogyria (BFPP). Disease-associated mutations in G1 studied to date are believed to induce complete loss of receptor function, either through disruption of receptor trafficking or signaling activity. Given that N-terminal truncation of G1 and other adhesion G protein-coupled receptors has been shown to significantly increase the receptors' constitutive signaling, we examined two different BFPP-inducing extracellular loop mutations (R565W and L640R) in the context of both full-length and N-terminally truncated (deltaNT) G1. Interestingly, we found that these mutations reduced surface expression of full-length G1 but not G1-deltaNT in HEK-293 cells. Moreover, the mutations ablated receptor-mediated activation of serum response factor luciferase, a classic measure of Galpha12/13-mediated signaling, but had no effect on G1-mediated signaling to nuclear factor of activated T cells (NFAT) luciferase. Given these differential signaling results, we sought to further elucidate the pathway by which G1 can activate NFAT luciferase. We found no evidence that deltaNT activation of NFAT is dependent on Galphaq/11-mediated or beta-arrestin-mediated signaling, but rather involves liberation of G beta gamma subunits and activation of calcium channels. These findings reveal that disease-associated mutations to the extracellular loops of G1 differentially alter receptor trafficking, depending on the presence of the N-terminus, and also differentially alter signaling to distinct downstream pathways.
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