Article
Multidisciplinary Sciences
Kirill D. Nadezhdin, Leonor Correia, Chamali Narangoda, Dhilon S. Patel, Arthur Neuberger, Thomas Gudermann, Maria G. Kurnikova, Vladimir Chubanov, Alexander I. Sobolevsky
Summary: The transient receptor potential channel TRPM7 is a crucial regulator of divalent cation balance in the body, impacting various biological processes such as embryonic development, immune responses, and cell functionalities. It is linked to neuronal and cardiovascular disorders as well as tumor progression, highlighting its potential as a drug target. Using cryo-EM, functional analysis, and molecular dynamics simulations, researchers have unraveled two distinct structural mechanisms behind TRPM7 activation through gain-of-function mutations and the agonist naltriben. These mechanisms exhibit different conformational dynamics and involve different domains. Additionally, the study identifies a binding site for potent and selective inhibitors that stabilize the closed state of TRPM7, paving the way for the development of drugs targeting TRPM7-related channelopathies.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Roberta Gualdani, Philippe Gailly, Jun-Hui Yuan, Xavier Yerna, Giulia Di Stefano, Andrea Truini, Giorgio Cruccu, Sulayman D. Dib-Hajj, Stephen G. Waxman
Summary: This study found that a variant in the TRPM7 channel, p.Ala931Thr, may be involved in the development of trigeminal neuralgia. The variant produced an abnormal inward Na+ current and increased excitability in trigeminal ganglion neurons, potentially underpinning the pain experienced by patients with trigeminal neuralgia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Man Liu, Hong Liu, Feng Feng, Esther Krook-Magnuson, Samuel C. Dudley
Summary: In this study, the researchers investigated the role of TRPM7 kinase in HypoMg-induced seizures and death. They found that inhibiting the kinase reduced inflammation and oxidative stress, suggesting that TRPM7 kinase function contributes to seizure-induced deaths in HypoMg mice.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
Yaopeng Hu, Qin Li, Lin-Hai Kurahara, Narumi Shioi, Keizo Hiraishi, Takayuki Fujita, Xin Zhu, Ryuji Inoue
Summary: The E7K mutation in the TRPM4 channel enhances channel function by altering its interaction with endogenous PIP2, potentially contributing to its arrhythmogenic potential.
Article
Cell Biology
Xing Gao, Chien-Wen Kuo, Alice Main, Elaine Brown, Francisco J. Rios, Livia De Lucca Camargo, Sheon Mary, Krzysztof Wypijewski, Caglar Gok, Rhian M. Touyz, William Fuller
Summary: This study identifies a new mechanism for regulating TrpM7 through palmitoylation. Palmitoylation controls the exit of TrpM7 from the endoplasmic reticulum and its distribution between the cell surface and intracellular vesicles. Palmitoylation is closely related to the ion channel activity and trafficking of TrpM7.
Article
Chemistry, Physical
Mahdi Ghorbani, Samarjeet Prasad, Jeffery B. Klauda, Bernard R. Brooks
Summary: The study introduces a machine learning method, GMVAE, which can perform dimensionality reduction and clustering of biomolecular conformations effectively. The model shows potential in analyzing the free energy landscape of protein folding, with highly separated clusters corresponding to metastable states during folding.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Engineering, Mechanical
Chuanlong Xu, Xiaobao Tian, Wentao Jiang, Qingyuan Wang, Haidong Fan
Summary: This study investigates the migration mechanisms of symmetric tilt grain boundaries (STGBs) in magnesium using molecular dynamic simulations. The results show that the migration mechanisms of grain boundaries are significantly influenced by their structure, with small angle STGBs migrating through twin nucleation and growth, large angle STGBs migrating through the glide of grain boundary dislocations, and medium angle STGBs transforming into twin boundaries through the emission of lattice dislocations/stacking faults.
INTERNATIONAL JOURNAL OF PLASTICITY
(2022)
Article
Biochemistry & Molecular Biology
Natalia Martinez-Gil, Oksana Kutsyr, Laura Fernandez-Sanchez, Xavier Sanchez-Saez, Henar Albertos-Arranz, Carla Sanchez-Castillo, Lorena Vidal-Gil, Nicolas Cuenca, Pedro Lax, Victoria Maneu
Summary: This study analyzed the role of transient receptor potential channel 7 (TRPM7) in retinal dysfunction associated with ischemia. Using an experimental model, the researchers observed a decrease in retinal responsiveness to light stimuli, reactive gliosis, and an increase in TRPM7 expression in Muller cells during ischemia. The findings suggest that TRPM7 could be a potential drug target for retinal pathologies related to ischemia.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Metallurgy & Metallurgical Engineering
Zhao-Qi Zhang, Hong-Yan Wang, Li Wang, Xiao-Bo Chen, Shao-Kang Guan, Cun-Guo Lin, Rong-Chang Zeng
Summary: This study investigates the protein adsorption mechanism on the surface of biodegradable magnesium alloys, revealing that MAO coating shows superior ability to capture proteins and improve cytocompatibility.
JOURNAL OF MAGNESIUM AND ALLOYS
(2022)
Article
Cell Biology
Anna Rossig, Kerstin Hill, Wolfgang Noerenberg, Sebastian Weidenbach, Susanna Zierler, Michael Schaefer, Thomas Gudermann, Vladimir Chubanov
Summary: This study identified three small synthetic molecules, iloperidone, ifenprodil, and VER155008, that selectively manipulate TRPM6 and TRPM7 currents.
Article
Biochemistry & Molecular Biology
Michael Brundl, Sarala Pellikan, Anna Stary-Weinzinger
Summary: ATP-sensitive potassium (K-ATP) channels consist of Kir6.2 pore and SUR domains, dysfunction linked to diseases, gating regulated by conformational changes and ligands including PIP2 activation. Structural information combined with functional data reveals the mechanism underlying Kir6.2 channel regulation by PIP2.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Lisandra Flores-Aldama, Daniel Bustos, Deny Cabezas-Bratesco, Wendy Gonzalez, Sebastian E. Brauchi
Summary: TRPV5 and TRPV6 are calcium-selective ion channels that play a crucial role in maintaining systemic calcium homeostasis. These channels are regulated by intracellular calcium, which induces inactivation. The inactivation of TRPV5 and TRPV6 can be divided into fast and slow phases, with the fast inactivation being unique to TRPV6. By utilizing various techniques, including structural analyses and mutagenesis, we have identified specific amino acids and interactions that govern the inactivation kinetics of mammalian TRPV5 and TRPV6 channels. Additionally, we propose that the association between the intracellular HLH domain and the TRP domain helix contributes to the faster inactivation kinetics observed in mammalian TRPV6 channels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, Research & Experimental
Noushafarin Khajavi, Andreas Beck, Klea Ricku, Philipp Beyerle, Katharina Jacob, Sabrina F. Syamsul, Anouar Belkacemi, Peter S. Reinach, Pascale C. F. Schreier, Houssein Salah, Tanja Popp, Aaron Novikoff, Andreas Breit, Vladimir Chubanov, Timo D. Mueller, Susanna Zierler, Thomas Gudermann
Summary: TRPM7 kinase is a potential regulator of insulin synthesis, beta cell dynamics, and glucose homeostasis. Its deletion disrupts insulin secretion and leads to glucose intolerance.
Article
Biology
Shashank Pant, Jiaren Zhang, Eung Chang Kim, Kin Lam, Hee Jung Chung, Emad Tajkhorshid
Summary: Research using molecular dynamics simulations and electrophysiology has revealed the allosteric role of phosphatidylinositol-4,5-bisphosphate (PIP2) in the activation of K(v)7.2 channels, influencing protein conformation and correlated motions.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Serge Hardy, Yevgen Zolotarov, Jacob Coleman, Simon Roitman, Hira Khursheed, Isabelle Aubry, Noriko Uetani, Michel L. Tremblay
Summary: Phosphatases of regenerating liver (PRL-1, PRL-2, PRL-3) and their interaction with CNNM magnesium transport regulators play a crucial role in controlling intracellular magnesium levels. This study reveals the dynamic regulation of TRPM7 function in response to PRL-1/2 levels, coordinating magnesium transport and cellular metabolism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Pharmacology & Pharmacy
Maria V. Yelshanskaya, Appu K. Singh, Chamali Narangoda, Robin S. B. Williams, Maria G. Kurnikova, Alexander I. Sobolevsky
Summary: This study characterized the interaction of trans-4-butylcyclohexane carboxylic acid (4-BCCA) with AMPA receptors, revealing it acts as a low-affinity inhibitor at specific sites in the transmembrane domain. The dynamic binding of 4-BCCA at these sites distinguishes it from other inhibitors like perampanel and ion channel blockers. Further research may explore the potential synergistic use of these inhibitors in treating epilepsy and other neurological disorders.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Roland Immler, Wiebke Nadolni, Annika Bertsch, Vasilios Morikis, Ina Rohwedder, Sergi Masgrau-Alsina, Tobias Schroll, Anna Yevtushenko, Oliver Soehnlein, Markus Moser, Thomas Gudermann, Eytan R. Barnea, Markus Rehberg, Scott Simon, Susanna Zierler, Monika Pruenster, Markus Sperandio
Summary: This study reveals the critical role of the voltage-gated potassium channel K(V)1.3 in calcium signaling and neutrophil trafficking during acute inflammatory processes. The findings provide evidence for the involvement of K(V)1.3 in key functions of neutrophils and suggest new therapeutic approaches for treating inflammatory disorders.
CARDIOVASCULAR RESEARCH
(2022)
Article
Multidisciplinary Sciences
Leonid Pereyaslavets, Ganesh Kamath, Oleg Butin, Alexey Illarionov, Michael Olevanov, Igor Kurnikov, Serzhan Sakipov, Igor Leontyev, Ekaterina Voronina, Tyler Gannon, Grzegorz Nawrocki, Mikhail Darkhovskiy, Ilya Ivahnenko, Alexander Kostikov, Jessica Scaranto, Maria G. Kurnikova, Suvo Banik, Henry Chan, Michael G. Sternberg, Subramanian K. R. S. Sankaranarayanan, Brad Crawford, Jeffrey Potoff, Michael Levitt, Roger D. Kornberg, Boris Fain
Summary: The main goal of molecular simulation is to accurately predict experimental observables of molecular systems, as well as to devise models for arbitrary neutral organic molecules. Researchers have successfully computed the solvation free energies of a diverse set of organic compounds using a polarizable force field fitted entirely to ab initio calculations, achieving high predictive accuracy.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Barbara Spix, Elisabeth S. Butz, Cheng-Chang Chen, Anna Scotto Rosato, Rachel Tang, Aicha Jeridi, Veronika Kudrina, Eva Plesch, Philipp Wartenberg, Elisabeth Arlt, Daria Briukhovetska, Meshal Ansari, Gizem Gunes Gunsel, Thomas M. Conlon, Amanda Wyatt, Sandra Wetzel, Daniel Teupser, Lesca M. Holdt, Fabien Ectors, Ingrid Boekhoff, Ulrich Boehm, Jaime Garcia-Anoveros, Paul Saftig, Martin Giera, Sebastian Kobold, Herbert B. Schiller, Susanna Zierler, Thomas Gudermann, Christian Wahl-Schott, Franz Bracher, Ali Oender Yildirim, Martin Biel, Christian Grimm
Summary: The study reveals TRPML3 as a key regulator of MMP-12 clearance by alveolar macrophages, suggesting it as a therapeutic target for emphysema and chronic obstructive pulmonary disease.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Andreea L. Turcu, Julia Companys-Alemany, Matthew B. Phillips, Dhilon S. Patel, Christian Grinan-Ferre, M. Isabel Loza, Jose M. Brea, Belen Perez, David Soto, Francesc X. Sureda, Maria G. Kurnikova, Jon W. Johnson, Merce Pallas, Santiago Vazquez
Summary: This study discovered a series of memantine analogs and investigated their pharmacological properties and effects. Among them, compound IIc showed strong NMDAR blocking ability and had positive effects on cognition and locomotion in Caenorhabditis elegans and 5XFAD mice.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Maria V. Yelshanskaya, Dhilon S. Patel, Christopher M. Kottke, Maria G. Kurnikova, Alexander I. Sobolevsky
Summary: This study reveals the number of agonist binding domains required for ion channel opening and the impact of agonist binding on channel conductance in AMPA subtype ionotropic glutamate receptors. By combining structural analysis with experimental results, molecular dynamics simulations, and machine learning analysis, we found that at least two agonist binding domains are necessary for channel opening, and binding of agonist to all four domains does not guarantee maximal channel conductance.
Article
Multidisciplinary Sciences
Madeleine R. Wilcox, Aparna Nigam, Nathan G. Glasgow, Chamali Narangoda, Matthew B. Phillips, Dhilon S. Patel, Samaneh Mesbahi-Vasey, Andreea L. Turcu, Santiago Vazquez, Maria G. Kurnikova, Jon W. Johnson
Summary: The study reveals that NMDA receptor channel blockers can access their binding site through two routes, providing insights into their mechanisms of action. This finding is important for understanding the neural signal transmission.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Filipp Gusev, Evgeny Gutkin, Maria G. Kurnikova, Olexandr Isayev
Summary: In this study, an efficient automated workflow was developed to identify compounds with the lowest binding free energy among thousands of congeneric ligands, which required only hundreds of thermodynamics integration calculations. The combination of active learning and automated machine learning allowed unbiased and efficient search for a small set of best-performing molecules. By applying this workflow to select inhibitors of the SARS-CoV-2 papain-like protease, 133 compounds with improved binding affinity, including 16 compounds with more than 100-fold improvement, were identified. The results demonstrate that the combination of active learning, automated machine learning, and free energy simulations provides a speedup of at least 20x compared to traditional expert-guided approaches.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Grzegorz Nawrocki, Igor Leontyev, Serzhan Sakipov, Mikhail Darkhovskiy, Igor Kurnikov, Leonid Pereyaslavets, Ganesh Kamath, Ekaterina Voronina, Oleg Butin, Alexey Illarionov, Michael Olevanov, Alexander Kostikov, Ilya Ivahnenko, Dhilon S. Patel, Subramanian K. . R. S. Sankaranarayanan, Maria G. Kurnikova, Christopher Lock, Gavin E. Crooks, Michael Levitt, Roger D. Kornberg, Boris Fain
Summary: Protein-ligand binding free-energy calculations using molecular dynamics simulations can be effectively performed using the ARROW force field. The ARROW force field, which is based on high-level quantum mechanical calculations, accurately predicts the binding free energies of various protein-ligand systems. The predictions made by ARROW show a similar accuracy level as leading nonpolarizable force fields.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Immunology
Tina Jooss, Jiong Zhang, Bela Zimmer, Tanja Rezzonico-Jost, Bjoern Rissiek, Penelope Felipe Pelczar, Frauke Seehusen, Friedrich Koch-Nolte, Tim Magnus, Susanna Zierler, Samuel Huber, Michael Schemann, Fabio Grassi, Annette Nicke
Summary: Blocking or deleting the pro-inflammatory P2X7 receptor channel can reduce tissue damage and symptoms in models of inflammatory bowel disease. P2X7 receptors on enteric neurons were suggested to mediate neuronal death and associated motility changes. However, this study found that P2X7 was not detected in neurons but were dominantly expressed in glia and macrophages, which interact closely with neurons. The overexpression of P2X7 did not induce significant pathological effects.
MUCOSAL IMMUNOLOGY
(2023)
Article
Medicine, Research & Experimental
Noushafarin Khajavi, Andreas Beck, Klea Ricku, Philipp Beyerle, Katharina Jacob, Sabrina F. Syamsul, Anouar Belkacemi, Peter S. Reinach, Pascale C. F. Schreier, Houssein Salah, Tanja Popp, Aaron Novikoff, Andreas Breit, Vladimir Chubanov, Timo D. Mueller, Susanna Zierler, Thomas Gudermann
Summary: TRPM7 kinase is a potential regulator of insulin synthesis, beta cell dynamics, and glucose homeostasis. Its deletion disrupts insulin secretion and leads to glucose intolerance.
Article
Multidisciplinary Sciences
Kirill D. Nadezhdin, Leonor Correia, Chamali Narangoda, Dhilon S. Patel, Arthur Neuberger, Thomas Gudermann, Maria G. Kurnikova, Vladimir Chubanov, Alexander I. Sobolevsky
Summary: The transient receptor potential channel TRPM7 is a crucial regulator of divalent cation balance in the body, impacting various biological processes such as embryonic development, immune responses, and cell functionalities. It is linked to neuronal and cardiovascular disorders as well as tumor progression, highlighting its potential as a drug target. Using cryo-EM, functional analysis, and molecular dynamics simulations, researchers have unraveled two distinct structural mechanisms behind TRPM7 activation through gain-of-function mutations and the agonist naltriben. These mechanisms exhibit different conformational dynamics and involve different domains. Additionally, the study identifies a binding site for potent and selective inhibitors that stabilize the closed state of TRPM7, paving the way for the development of drugs targeting TRPM7-related channelopathies.
NATURE COMMUNICATIONS
(2023)
