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
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
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)
Article
Biochemistry & Molecular Biology
Elaine Yang, Weiming Bu, Antonio Suma, Vincenzo Carnevale, Kimberly C. Grasty, Patrick J. Loll, Kellie Woll, Natarajan Bhanu, Benjamin A. Garcia, Roderic G. Eckenhoff, Manuel Covarrubias
Summary: This study utilized PAL technique and MD simulation to uncover the mechanism through which propofol inhibits Nay channel function by promoting activation-coupled inactivation, while also providing direct insights into the structural basis of propofol modulation of Nay channels.
ACS CHEMICAL NEUROSCIENCE
(2021)
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
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)
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
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)
Article
Chemistry, Analytical
Henry West, Gavin E. Reid
Summary: Sterols, a class of lipid molecules, play critical functional roles in mammalian biology and are commonly analyzed using high performance liquid chromatography coupled with tandem mass spectrometry. This study explores novel approaches, including 213 nm photodissociation MS/MS and hybrid multistage-MS/MS, for improved structural characterization of sterol lipids, showing promising results in isomeric differentiation of oxysterols. The research demonstrates the potential of using UVPD-MS/MS and hybrid collision induced-MS/MS approaches for enhanced analysis of sterol lipids.
ANALYTICA CHIMICA ACTA
(2021)
Article
Biochemistry & Molecular Biology
Akshay Sridhar, Sarah C. R. Lummis, Diletta Pasini, Aujan Mehregan, Marijke Brams, Kumiko Kambara, Daniel Bertrand, Erik Lindahl, Rebecca J. Howard, Chris Ulens
Summary: This study reveals a potential lipid-binding site at a residue in the ELIC channel's transmembrane domain, with simulations showing preferential binding of positively charged lipids, particularly interacting with residue W206, through cation-pi binding. Polar contacts from other regions of the protein and mutagenesis experiments further support lipid binding. Mutations at this site in GABA(A) receptors can alter the affinity of the agonist response, suggesting a potential role in channel gating.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemical Research Methods
Marc A. Damgen, Philip C. Biggin
Summary: The study on pentameric ligand-gated ion channels (pLGICs) using molecular dynamics simulations revealed key lipid-protein interactions dependent on the channel state, potentially aiding in the design of lipid-like allosteric drugs in the future.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Ivan Felsztyna, Marcos A. Villarreal, Daniel A. Garcia, Virginia Miguel
Summary: This study evaluated the usability of homology models in virtual screening (VS) for the RDL receptor, a relevant protein target for insecticide molecules. The impact of template conformational states on VS performance was analyzed. Homology models based on different pLGIC templates representing closed, open, and desensitized states were obtained. Their performance in prioritizing active ligands was assessed, and the best-performing models were subjected to molecular dynamics simulations. The results showed that the structural properties of the binding site and the template conformational state influenced the VS performance. Models with more constricted binding cavities tended to have better performance, and the closed conformation template produced the best results. These findings provide guidance for the application of homology modeling in virtual screening for other proteins in the pLGIC family.
Article
Biochemistry & Molecular Biology
Alessandro Crnjar, Susanne M. Mesoy, Sarah C. R. Lummis, Carla Molteni
Summary: Pentameric ligand-gated ion channels (pLGICs) play a crucial role in fast synaptic transmission and are important drug targets. The M4 helix is key to channel opening, connecting radially through M1 to the hydrophobic gate on the pore-lining helix M2.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Michele Bachmann, Audrey Ortega-Ramirez, Lilia Leisle, Stefan Gruender
Summary: Researchers successfully expressed HyNaC2/3/5 channels in human HEK 293 and monkey COS-7 cells, with increased protein expression and current amplitude through codon optimization. They used this improved expression to perform Ca2+ imaging and demonstrate the glycosylation pattern of the channels.
Meeting Abstract
Biophysics
Wayland W. L. Cheng
BIOPHYSICAL JOURNAL
(2019)
Article
Biochemistry & Molecular Biology
Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Allison L. Germann, Daniel J. Shin, Krishnan Kathiresan, Ming-Xing Qian, Brad Manion, Wayland W. L. Cheng, David E. Reichert, Gustav Akk, Douglas F. Covey, Alex S. Evers
Article
Biochemistry & Molecular Biology
Yusuke Sugasawa, John R. Bracamontes, Kathiresan Krishnan, Douglas F. Covey, David E. Reichert, Gustav Akk, Qiang Chen, Pei Tang, Alex S. Evers, Wayland W. L. Cheng
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Wayland W. L. Cheng, Melissa M. Budelier, Yusuke Sugasawa, Lucie Bergdoll, Maria Queralt-Martin, William Rosencrans, Tatiana K. Rostovtseva, Zi-Wei Chen, Jeff Abramson, Kathiresan Krishnan, Douglas F. Covey, Julian P. Whitelegge, Alex S. Evers
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2019)
Article
Biology
Ailing Tong, John T. Petroff, Fong-Fu Hsu, Philipp A. M. Schmidpeter, Crina M. Nimigean, Liam Sharp, Grace Brannigan, Wayland W. L. Cheng
Article
Chemistry, Analytical
John T. Petroff, Ailing Tong, Lawrence J. Chen, Gregory T. Dekoster, Farha Khan, Jeff Abramson, Carl Frieden, Wayland W. L. Cheng
ANALYTICAL CHEMISTRY
(2020)
Article
Pharmacology & Pharmacy
Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers, Joe Henry Steinbach
MOLECULAR PHARMACOLOGY
(2020)
Article
Biology
Yusuke Sugasawa, Wayland W. L. Cheng, John R. Bracamontes, Zi-Wei Chen, Lei Wang, Allison L. Germann, Spencer R. Pierce, Thomas C. Senneff, Kathiresan Krishnan, David E. Reichert, Douglas F. Covey, Gustav Akk, Alex S. Evers
Article
Biochemistry & Molecular Biology
Kathiresan Krishnan, Mingxing Qian, McKenna Feltes, Zi-Wei Chen, Sarah Gale, Lei Wang, Yusuke Sugasawa, David E. Reichert, Jean E. Schaffer, Daniel S. Ory, Alex S. Evers, Douglas F. Covey
Summary: Cholesterol analogues containing aliphatic diazirine or TPD groups were used as photoaffinity labeling reagents to study cholesterol binding sites on GLIC. The probes showed differences in photolabeling efficiencies and residues identified, indicating complementary information provided by the two classes of probes. Photoaffinity labeling using these reagents in mammalian cell membranes revealed differences in the pattern of labeled proteins, highlighting their utility in future studies of cholesterol biology.
ACS CHEMICAL BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Allison L. Germann, Spencer R. Pierce, Hiroki Tateiwa, Yusuke Sugasawa, David E. Reichert, Alex S. Evers, Joe Henry Steinbach, Gustav Akk
Summary: Previous work has identified three distinct binding sites for potentiating steroids in the heteromeric GABA(A) receptor, with mutations in these sites showing independent and additive effects. The findings suggest that mutations in sites I and II have energetically additive effects, while mutations in site III do not affect potentiation by the steroid. The results indicate that steroid actions at each binding site are independent.
MOLECULAR PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Chenchen Bian, Xiangtong Yuan, Caihong Zeng, Jian Sun, Gen Kaneko, Hong Ji
Summary: This study investigated the mechanism of docosahexaenoic acid (DHA)-induced apoptosis mediated by mitophagy, using grass carp as an animal model. The results showed that inhibition of mitophagy alleviated apoptosis and eliminated the inhibition of lipid accumulation induced by DHA. Mechanistically, DHA induced mitophagy by activating the PPAR gamma-LC3-BNIP3 pathway. Inhibition of PPAR gamma decreased autophagy-related gene expression and prevented BNIP3/NIX-mediated mitophagy-induced apoptosis, thereby alleviating the inhibition of lipid accumulation.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)
Article
Biochemistry & Molecular Biology
Venkatesan Ramya, Karuppiah Prakash Shyam, Arulanandu Angelmary, Balamuthu Kadalmani
Summary: This study reveals that Lauric acid (LA) exerts an epigenetic regulation and metabolic reprogramming on SH-SY5Y neuroblastoma cells through modulation of lncRNA HOTAIR, remodeling of chromatin H3K4 tri-methylation and regulation of glucose uptake by controlling NF-kappa B activation.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)
Article
Biochemistry & Molecular Biology
Sreelekshmi Sreekumar, Karyath Palliyath Gangaraj, Manikantan Syamala Kiran
Summary: This study investigates the intricate interplay between angiogenic regulation and the browning of white adipocytes. The findings reveal that concurrent activation of angiogenesis is necessary for inducing browning of white adipocytes. The study also highlights the role of Vascular endothelial growth factor (VEGF) in promoting angiogenesis and triggering the browning process through the activation of Estrogen receptor alpha (ER alpha) signaling pathway.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)
Article
Biochemistry & Molecular Biology
Zanxia Cao, Liling Zhao, Mingcui Chen, Zhihong Shi, Lei Liu
Summary: This study investigated the translocation process of cholesterol/calcitriol in bacterial membranes and their effects on membrane structure. Calcitriol facilitated water transport across the membrane, while cholesterol had the opposite effect. These findings contribute to a better understanding of the relationship between cholesterol/calcitriol concentrations, lipid bilayer structure, and water permeation.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)
Article
Biochemistry & Molecular Biology
Xiaozhen Guo, Jiawen Wang, Hualing Xu, Yangyang Wang, Yutang Cao, Yingquan Wen, Jiaqi Li, Yameng Liu, Kanglong Wang, Jue Wang, Xianchun Zhong, Chuying Sun, Yongxin Zhang, Jingyi Xu, Cuina Li, Pengxiang Mu, Lingyan Xu, Cen Xie
Summary: This study aims to investigate the role of the gut microbiota-bile acid axis in regulating the diurnal rhythms of metabolic homeostasis and assess the impact of obesity on them. The results show that high fat diet feeding and Leptin gene deficiency disrupt the rhythmic patterns of insulin sensitivity and serum total cholesterol levels. The study provides compelling evidence for the association between diurnal rhythm of insulin sensitivity and gut microbiota-bile acid axis, and elucidates the deleterious effects of obesity on gut microbiome-bile acid metabolism.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)
Article
Biochemistry & Molecular Biology
Giuseppe Pepe, Maria Cotugno, Federico Marracino, Luca Capocci, Ludovica Pizzati, Maurizio Forte, Rosita Stanzione, Pamela Scarselli, Alba Di Pardo, Sebastiano Sciarretta, Massimo Volpe, Speranza Rubattu, Vittorio Maglione
Summary: The study found that enzymes involved in sphingolipid metabolism show abnormal expression in the cardiac tissue of hypertensive rat models, which may be related to the susceptibility to cardiac damage.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2024)