Article
Multidisciplinary Sciences
Marie Lycksell, Urska Rovsnik, Anton Hanke, Anne Martel, Rebecca J. Howard, Erik Lindahl
Summary: This study characterized the structure and dynamics of DeCLIC using cryo-EM, SANS, and MD simulations, revealing alternative conformations of the NTD and calcium-binding site and expanding the conformational landscape of the pLGIC family. Moreover, it demonstrated the power of combining low-resolution scattering, high-resolution structural, and MD simulation data to elucidate highly conserved interfacial interactions in the pLGIC family.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Mykhaylo Slobodyanyuk, Mackenzie J. Thompson, Rebecca A. Dean, John E. Baenziger, Roberto A. Chica, Corrie J. B. DaCosta
Summary: A study on the prokaryotic ligand-gated ion channel ELIC provides insights into the origin of agonism and antagonism at nicotinic acetylcholine receptors. Acetylcholine acts as an agonist in acetylcholine receptors but as an antagonist in ELIC. By substituting important residues in the agonist-binding site of ELIC, the apparent affinity for acetylcholine is reduced, demonstrating different roles of these residues in different contexts. The study also highlights a mechanism of antagonism where agonists with appreciable affinity but no efficacy can act as competitive antagonists.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biology
Cathrine Bergh, Stephanie A. Heusser, Rebecca Howard, Erik Lindahl
Summary: The study utilized enhanced sampling to simulate the pH-gated channel GLIC and construct Markov state models of gating, revealing differential effects of protonation and mutation on channel states, estimation of open probabilities and transition rates, as well as state- and protonation-dependent symmetrization.
Article
Biology
Noah M. Dietzen, Mark J. Arcario, Lawrence J. Chen, John T. Petroff, K. Trent Moreland, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, Wayland W. L. Cheng
Summary: Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs), but the specific mechanism of inhibition is unclear. This study found that docosahexaenoic acid (DHA), a type of PUFA, is more effective at inhibiting the ELIC receptor's response to agonists compared to other fatty acids. Using experiments and simulations, the researchers identified two binding sites for fatty acids in the outer transmembrane domain (TMD) of ELIC, and demonstrated that DHA selectively binds to these sites and inhibits ELIC by binding to a specific intrasubunit site.
Review
Physiology
Wayland W. L. Cheng, Mark J. Arcario, John T. Petroff
Summary: Lipids modulate the function of ion channels through direct lipid-protein interactions. Cryo-EM studies have identified lipid binding sites on ion channels, but the role of these sites in lipid modulation is not fully understood. These binding sites also coincide with sites for other allosteric modulators or drugs, suggesting that lipids act as endogenous allosteric modulators. This review focuses on lipid-drug binding sites in pentameric ligand-gated ion channels and transient receptor potential channels, highlighting the shared sites for phospholipids, sterols, anesthetics, and vanilloids. The implications of lipid binding at these sites, such as potential changes in drug potency and guiding drug design through protein-lipid interactions, are discussed. However, further studies are needed to fully understand the mechanisms of lipid modulation at these sites.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Ryan Gallagher, Taima Qudah, Thomas Balle, Mary Chebib, Malcolm D. McLeod
Summary: Analogues of methyllycaconitine (MLA) incorporating modified ester sidechains were designed and synthesized, showing selective non-competitive inhibition for specific nAChR subtypes. This study defines the biological effects of MLA analogues more clearly and identifies strategies for developing selective ligands for the alpha 4 beta 2 nAChR subtype.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Filip Koniuszewski, Florian D. Vogel, Konstantina Bampali, Jure Fabjan, Thomas Seidel, Petra Scholze, Philip B. Schmiedhofer, Thierry Langer, Margot Ernst
Summary: This study explores the potential for polypharmacology among pLGICs, revealing that ligands can interact with homologous sites in many members of the superfamily and multiple pockets in distinct localizations of individual receptor subtypes share common ligands. This poses challenges for the development of selective agents.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Neurosciences
Iris Hardege, Julia Morud, Amy Courtney, William R. Schafer
Summary: This study identifies multiple new inhibitory ion channels with diverse ligand activation properties in Caenorhabditis elegans. These channels have inhibitory effects on acetylcholine and also show both excitatory and inhibitory effects on other major neurotransmitters. The findings shed light on the important role of diverse ligand-gated ion channels in generating complexity in a compact anatomical nervous system.
JOURNAL OF NEUROSCIENCE
(2023)
Review
Biochemistry & Molecular Biology
Anna Ananchenko, Toka O. K. Hussein, Deepansh Mody, Mackenzie J. Thompson, John E. Baenziger
Summary: Pentameric ligand-gated ion channels (pLGICs) play a crucial role in synaptic communication and are considered important targets for treating neurological disorders. Lipids and lipophilic compounds modulate pLGIC function, and recent structural and biophysical data have identified binding sites for lipids on pLGICs.
Article
Multidisciplinary Sciences
Shuo Han, Xiang-Ping Chu, Ryan Goodson, Prae Gamel, Sophia Peng, Joshua Vance, Shizhen Wang
Summary: Cholesterol inhibits the hHv1 channel by stabilizing the voltage-sensing S4 segment at resting conformations, providing a mechanism for the regulation of fertilization by the hHv1 channel.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Rebecca J. Howard
Summary: The superfamily of pentameric ligand-gated ion channels plays crucial roles in electrochemical signal transduction across evolution, with increasing structural studies focusing on three model subfamilies. Common themes include gating mechanisms and diversity beyond the protein level.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Agronomy
Andrew K. Jones, Delphine Goven, Josy-Anne Froger, Alexandre Bantz, Valerie Raymond
Summary: The cysLGIC superfamilies of Blattella germanica and Periplaneta americana are the largest insect cysLGIC superfamilies characterized to date, with 30 and 32 subunit-encoding genes, respectively. These cockroaches possess ion channels predicted to be gated by acetylcholine, gamma-aminobutyric acid, glutamate, histamine, as well as orthologues of the drosophila pH-sensitive chloride channel (pHCl), CG8916 and CG12344. The diversity of the cockroach cysLGICs is broadened by alternative splicing and RNA A-to-I editing.
PEST MANAGEMENT SCIENCE
(2021)
Article
Multidisciplinary Sciences
John T. Petroff, Noah M. Dietzen, Ezry Santiago-McRae, Brett Deng, Maya S. Washington, Lawrence J. Chen, K. Trent Moreland, Zengqin Deng, Michael Rau, James A. J. Fitzpatrick, Peng Yuan, Thomas T. Joseph, Jerome Henin, Grace Brannigan, Wayland W. L. Cheng
Summary: The model pLGIC ELIC is positively modulated by the anionic phospholipid phosphatidylglycerol, which stabilizes the activated, open-channel state of the pLGIC.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Makoto Ihara
Summary: The Cys-loop superfamily of ligand-gated ion channels is widely present in vertebrates and invertebrates, serving as targets for various classes of pesticides. These pesticides have high target site selectivity, contributing to their safety in insecticide use. Structural analyses, particularly X-ray crystal structures, have revealed details of molecular interactions between insecticides and their targets, aiding in understanding the mechanisms of neuroactive insecticides targeting these ion channels.
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yipeng Cao, Rui Yang, Wei Wang, Shengpeng Jiang, Chengwen Yang, Qingxin Wang, Ningbo Liu, Yi Xue, Imshik Lee, Xiangfei Meng, Zhiyong Yuan
Summary: Protein-lipid interactions play a crucial role in the function of membrane ion-channel proteins, which should be considered along with the diversity and complexity of membrane lipid composition. In this study, the distribution of different lipids in the membrane and the structure and conductance properties of phospholamban (PLN) pentamers were investigated through molecular dynamics simulations. The results suggest that cholesterol enriches around the protein, stabilizing the structure of PLN pentamers. The absence of cholesterol increases the flexibility of the protein backbone and lowers the energy barrier for ion permeation.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Tommy S. Tillman, Zachary Choi, Yan Xu, Pei Tang
ACS CHEMICAL NEUROSCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Elliot A. Philips, Antonio Garcia-Espana, Anna S. Tocheva, Ian M. Ahearn, Kieran R. Adam, Ruimin Pan, Adam Mor, Xiang-Peng Kong
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Joel Caporoso, Mark Moses, Kerryann Koper, Tommy S. Tillman, Lingling Jiang, Nicole Brandon, Qiang Chen, Pei Tang, Yan Xu
ACS CHEMICAL NEUROSCIENCE
(2020)
Article
Microbiology
Manxue Jia, Rachel A. Liberatore, Yicheng Guo, Kun-Wei Chan, Ruimin Pan, Hong Lu, Eric Waltari, Eva Mittler, Kartik Chandran, Andres Finzi, Daniel E. Kaufmann, Michael S. Seaman, David D. Ho, Lawrence Shapiro, Zizhang Sheng, Xiang-Peng Kong, Paul D. Bieniasz, Xueling Wu
CELL HOST & MICROBE
(2020)
Article
Virology
Rebecca L. Powell, Svenja Weiss, Alisa Fox, Xiaomei Liu, Vincenza Itri, Xunqing Jiang, Christina C. Luo, David A. Spencer, Shilpi Pandey, Tracy Cheever, Deborah H. Fuller, Maxim Totrov, Ann J. Hessell, Nancy L. Haigwood, Xiang-Peng Kong, Susan Zolla-Pazner
JOURNAL OF VIROLOGY
(2020)
Article
Biochemistry & Molecular Biology
Lisa J. Clark, James Krieger, Alex D. White, Vasyl Bondarenko, Saifei Lei, Fei Fang, Ji Young Lee, Pemra Doruker, Thore Bottke, Frederic Jean-Alphonse, Pei Tang, Thomas J. Gardella, Kunhong Xiao, Ieva Sutkeviciute, Irene Coin, Ivet Bahar, Jean-Pierre Vilardaga
NATURE CHEMICAL BIOLOGY
(2020)
Article
Virology
Santhi Devasundaram, Margherita Rosati, Antonio Valentin, Svenja Weiss, Vincenza Itri, Hung V. Trinh, Jenifer Bear, Bhabadeb Chowdhury, Celia C. LaBranche, David Montefiori, Guido Ferrari, Mangala Rao, Xiang-Peng Kong, Susan Zolla-Pazner, George N. Pavlakis, Barbara K. Felber
Summary: Priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection. This work demonstrates that focusing immune responses on the V1V2 region through DNA priming vaccination induces improved recognition of epitopes important for protective immunity, particularly V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial.
JOURNAL OF VIROLOGY
(2021)
Article
Microbiology
Chitra Upadhyay, Roya Feyznezhad, Liwei Cao, Kun-Wei Chan, Kevin Liu, Weiming Yang, Hui Zhang, Jason Yolitz, James Arthos, Arthur Nadas, Xiang-Peng Kong, Susan Zolla-Pazner, Catarina E. Hioe
Article
Multidisciplinary Sciences
Jinglei Xiao, Vasyl Bondarenko, Yali Wang, Antonio Suma, Marta Wells, Qiang Chen, Tommy Tillman, Yan Luo, Buwei Yu, William P. Dailey, Roderic Eckenhoff, Pei Tang, Vincenzo Carnevale, Michael L. Klein, Yan Xu
Summary: This study identifies residue T140 in the S4-S5 linker of bacterial sodium channels as critical for channel activation and drug effects on inactivation. The drug propofol binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner, promoting and stabilizing inactivated states. The results provide direct evidence of distinct interactions between the S4-S5 linker and S6 helix in activated and inactivated states, pointing towards a potential direction for conformation-dependent drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Shuo Sui, Anne Mulichak, Raviraj Kulathila, Joshua McGee, Danny Filiatreault, Sarthak Saha, Aina Cohen, Jinhu Song, Holly Hung, Jonathan Selway, Christina Kirby, Om K. Shrestha, Wilhelm Weihofen, Michelle Fodor, Mei Xu, Rajiv Chopra, Sarah L. Perry
Summary: This novel approach utilizes capillary-based microfluidic devices and X-ray crystallography to accelerate the process of small-molecule-compound screening. The devices are designed for efficient sample manipulation and crystal handling, opening up new possibilities for research in this field.
JOURNAL OF APPLIED CRYSTALLOGRAPHY
(2021)
Article
Multidisciplinary Sciences
Vasyl Bondarenko, Marta M. Wells, Qiang Chen, Tommy S. Tillman, Kevin Singewald, Matthew J. Lawless, Joel Caporoso, Nicole Brandon, Jonathan A. Coleman, Sunil Saxena, Erik Lindahl, Yan Xu, Pei Tang
Summary: In this study, using a combination of experiments and computational methods, the full-length intracellular domain (ICD) structure of the human alpha 7 nicotinic acetylcholine receptor in a resting state was determined. It was found that a significant portion of the ICD residues are located in highly flexible regions, with a large loop (loop L) contributing to its stability by anchoring onto the MA helix. Known motifs for cytoplasmic binding, regulation, and signaling were observed in both helices and disordered flexible regions, highlighting the important role of ICD conformational plasticity in orchestrating various biological processes.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Izumi Ishigami, Silvia Russi, Aina Cohen, Syun-Ru Yeh, Denis L. Rousseau
Summary: This study investigated the relationship between the structural integrity of bovine CcO in the fully oxidized state and synchrotron radiation using microspectroscopy-coupled X-ray crystallography. The results showed that X-ray exposure caused the conversion of the oxidized state (O) to a hybrid state (O*) in which all four metal centers were reduced, but the protein matrix remained in the O conformation and the ligands in the BNC were intact. Annealing the O* crystal induced the relaxation of the structure to a new state (R*) where the protein matrix converted to the fully reduced R conformation, except for partial retention of the O conformation in helix X.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Galen J. Correy, Daniel W. Kneller, Gwyndalyn Phillips, Swati Pant, Silvia Russi, Aina E. Cohen, George Meigs, James M. Holton, Stefan Gahbauer, Michael C. Thompson, Alan Ashworth, Leighton Coates, Andrey Kovalevsky, Flora Meilleur, James S. Fraser
Summary: This study determined the crystal structures of the nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), revealing the reorganization of water networks upon binding of ADP-ribose and other ligands. The catalytic mechanism of coronavirus macrodomains was found to be distinct from that of human macrodomains, providing insights for the development of inhibitors.
Article
Biochemical Research Methods
Zhongrui Liu, Kevin K. Gu, Megan L. Shelby, Deepshika Gilbile, Artem Y. Lyubimov, Silvia Russi, Aina E. Cohen, Sankar Raju Narayanasamy, Sabine Botha, Christopher Kupitz, Raymond G. Sierra, Fredric Poitevin, Antonio Gilardi, Stella Lisova, Matthew A. Coleman, Matthias Frank, Tonya L. Kuhl
Summary: Over the past two decades, serial X-ray crystallography has made significant progress in determining the structures of proteins. This study presents an improved design of a polymer microfluidic chip that facilitates the delivery of fragile and small crystals to X-ray beams. The chip is customizable for different types of crystals and offers a user-friendly, cost-effective, and robust sample-delivery platform. Experimental results demonstrate the effectiveness of the chip design in obtaining high-resolution data sets for various proteins. The improved chip design provides a powerful sample-delivery tool for structural biologists, especially when working with limited sample volumes and fragile crystals.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Sarthak Saha, Can oezden, Alfred Samkutty, Silvia Russi, Aina Cohen, Margaret M. Stratton, Sarah L. Perry
Summary: Proteins are essential for various biological functions and their structure determines their function. X-ray crystallography is used to determine protein structure, but protein crystallization is required. We have developed a microfluidic device that can handle and measure fluids for protein crystallization without the need for additional connections. The use of UV-curable polymers allows for in situ X-ray crystallography, simplifying the analysis process. We demonstrate the device's utility using lysozyme and CaMKII beta as examples.