Article
Biochemistry & Molecular Biology
Mu Li, Xintong Zhang, Sixiang Chen, Hanhe Liu, Yuan-Wei Zhang
Summary: This study reveals a novel structural characteristic of the neurotransmitter sodium symporter (NSS) family, specifically in TuriSERT, and demonstrates the unique substrate binding site and 1:1 stoichiometry of sodium-substrate binding.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Emanuela Colucci, Zaid R. Anshari, Miyer F. Patino-Ruiz, Mariia Nemchinova, Jacob Whittaker, Dirk J. Slotboom, Albert Guskov
Summary: Episodic ataxias (EAs) are rare neurological conditions caused by mutations in the glutamate transporter protein EAAT1. In this study, the authors investigated how a specific mutation, P208R, affects the function and structure of the protein. They found that the mutation leads to reduced substrates transport and increased anion conductance, possibly due to the interaction between the mutant protein and the lipid environment.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Valentina Arkhipova, Haigen Fu, Mark W. H. Hoorens, Gianluca Trinco, Lucien N. Lameijer, Egor Marin, Ben L. Feringa, Gerrit J. Poelarends, Wiktor Szymanski, Dirk J. Slotboom, Albert Guskov
Summary: Photopharmacology addresses drug selectivity and side effects through the creation of light-activated photoresponsive molecules. However, the structural basis for light-induced modulation of inhibitory potency is still unclear, posing a major design challenge for this emerging field. Crystal structures of glutamate transporter homologue Glt(Tk) with photoresponsive inhibitors provide insight into the origins of photocontrol and lay the foundation for using photocontrolled ligands to study transporter dynamics.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Shengzhe Deng, Haiwei Zhang, Rongpei Gou, Ding Luo, Zerong Liu, Feng Zhu, Weiwei Xue
Summary: The study investigates the molecular mechanism underlying the transportation of human dopamine transporter (hDAT), which regulates the reuptake of extracellular dopamine (DA) and is an essential target for CNS diseases. Using a structure-based method, allosteric sites on hDAT in inward-open conformation were explored and compounds with allosteric affinity were screened. The discovery of a new allosteric inhibitor for hDAT provides a starting point for lead optimization and demonstrates the usability of the method for discovering novel allosteric modulators of other therapeutic targets.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Pharmacology & Pharmacy
Shreyas Bhat, Ali El-Kasaby, Michael Freissmuth, Sonja Sucic
Summary: Neurotransmitter transporters play a crucial role in the central nervous system, and dysfunction can lead to various neurological disorders such as epilepsy, intellectual disability, or Parkinson's disease. Recent studies have linked genetic point mutations in NTTs to the onset of neurological disorders and have identified some folding-deficient variants that can be rescued by small molecules.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Biochemical Research Methods
Mengyan Zhang, Maciej Bartosz Holowko, Huw Hayman Zumpe, Cheng Soon Ong
Summary: This study proposes a machine learning guided Design-Build-Test-Learn (DBTL) cycle for the experimental design of bacterial ribosome binding sites (RBSs). By integrating machine learning algorithms with laboratory automation and high-throughput processes, the researchers were able to reliably design small genetic parts with high translation initiation rates.
ACS SYNTHETIC BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Carmina Micelli, Yunfei Dai, Nicole Raustad, Ralph R. Isberg, Christopher G. Dowson, Adrian J. Lloyd, Edward Geisinger, Allister Crow, David I. Roper
Summary: Acinetobacter baumannii is a gram-negative bacterial pathogen that causes challenging nosocomial infections. The study reveals the molecular details of cell wall elongation inhibition upon zinc starvation in A. baumannii. The findings offer a perspective for dual inhibition of zinc-dependent peptidoglycan synthases and metallo-beta-lactamases by metal-chelating agents.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Analytical
Zan Gao, Guangfu Wu, Yang Song, Huijie Li, Yuxuan Zhang, Michael J. Schneider, Yingqi Qiang, Jackson Kaszas, Zhengyan Weng, He Sun, Bryan D. Huey, Rebecca Y. Lai, Yi Zhang
Summary: This study presents a flexible neural probe for multiplexed neurochemical monitoring using aptamers functionalized on graphene field-effect transistors (G-FETs). The neural probes demonstrate excellent flexibility, lightweight, and can monitor serotonin and dopamine with high sensitivity and selectivity. The developed methodology can be adapted for monitoring other neurochemicals.
ANALYTICAL CHEMISTRY
(2022)
Article
Biology
Zachary J. Frangos, Katie A. Wilson, Heather M. Aitken, Ryan Cantwell Chater, Robert J. Vandenberg, Megan L. O'Mara
Summary: This study investigates the binding of cholesterol to GlyT2 protein, its modulation of glycine transport rate, and its influence on the inhibition of GlyT2 by bioactive lipids. The results show that the recruitment of membrane cholesterol to a binding site formed by transmembrane helices 1, 5, and 7 modulates the inhibition of glycine transport. The synergy between cholesterol and allosteric inhibitors provides a novel mechanism for the development of alternative therapeutics for neuropathic pain and other SLC6 transporters.
LIFE SCIENCE ALLIANCE
(2023)
Article
Chemistry, Medicinal
Thomas M. Ackermann, Lars Allmendinger, Georg Hoefner, Klaus T. Wanner
Summary: This study introduces the first binding assay for GlyT2 using the concept of MS Binding Assays. By employing the selective GlyT2 inhibitor Org25543 as a reporter ligand, the study quantified its binding characteristics and determined the inhibitory constants of 19 GlyT ligands. By comparing the results with published inhibitory potencies from various functional assays, the validity of the GlyT2 affinities determined with the binding assay was confirmed.
Review
Neurosciences
Tomonori Furukawa, Atsuo Fukuda
Summary: During brain and spinal cord development, the inhibitory neurotransmitters GABA and glycine cause depolarization instead of hyperpolarization in adults. This is influenced by changes in the transmembrane chloride gradient, which is regulated by chloride transporters. The endogenous agonists for these receptors are not fully understood, but taurine is suggested to play a role in the development of neocortex by tonically activating GABA(A)Rs and modulating glycine receptors. Taurine also regulates chloride homeostasis through the WNK-SPAK/OSR1 signaling pathway.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Michelle J. Botha, Stewart B. Kirton
Summary: This study investigates the reasons for differences in affinity between monoamine transporters using various computational experiments. The results show that there is no direct correlation between scoring functions and experimental activity, but certain scoring functions and a consensus scoring approach are significantly correlated with the affinity of the transporters. Additionally, qualitative structure-activity relationship experiments generate predictive models but do not provide a deeper understanding of the differences in affinity between the transporters.
Article
Multidisciplinary Sciences
Dongxue Yang, Eric Gouaux
Summary: This study used cryo-electron microscopy structures to elucidate the structural states of SERT in different conditions, revealing all fundamental steps of the transport cycle. The research identified the substrate-bound allosteric site and provided new structural insights into how SERT controls the binding and unbinding of serotonin.
Article
Medicine, General & Internal
Feixia Zheng, Zhongdong Lin, Ying Hu, Xulai Shi, Qianlei Zhao, Zhenlang Lin
Summary: This study reports a novel non-canonical splice-site (NCSS) variant in a Chinese patient with cerebral adrenoleukodystrophy (CALD). By combining RNA sequencing (RNA-Seq) and whole-exome sequencing (WES) techniques, the study successfully diagnosed the patient and identified a new NCSS variant in the ABCD1 gene, expanding the spectrum of known variants and providing important insights for early diagnosis of CALD with NCSS variants.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Waqas Javed, Sylvain Vallet, Marie-Pierre Clement, Aline Le Roy, Martine Moulin, Michael Hartlein, Cecile Breyton, Odile Burlet-Schiltz, Julien Marcoux, Cedric Orelle, Christine Ebel, Anne Martel, Jean-Michel Jault
Summary: This study used small angle neutron scattering and hydrogen/deuterium exchange coupled to mass spectrometry to investigate the conformational states of the BmrA transporter during its ATPase cycle. The researchers found that under specific mutation conditions, the BmrA transporter can be trapped in an ATP-bound inward-facing conformation. Comparing the transition-like state induced by vanadate with the apo state or the presence of ADP/Mg, it was observed that in the post-hydrolytic step, the distances between the two nucleotide-binding domains appeared to be more separated but remained shorter than in the widest opening state found in the related transporter MsbA.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Review
Physiology
Cristina Fenollar-Ferrer, Lucy R. Forrest
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Edoardo Sarti, Antoniya A. Aleksandrova, Srujan K. Ganta, Amarendra S. Yavatkar, Lucy R. Forrest
NUCLEIC ACIDS RESEARCH
(2019)
Article
Physiology
Vanessa Leone, Izabela Waclawska, Katharina Kossmann, Caroline Koshy, Monika Sharma, Thomas F. Prisner, Christine Ziegler, Burkhard Endeward, Lucy R. Forrest
JOURNAL OF GENERAL PHYSIOLOGY
(2019)
Article
Multidisciplinary Sciences
Eva Hellsberg, Gerhard F. Ecker, Anna Stary-Weinzinger, Lucy R. Forrest
Article
Microbiology
Thomas C. Fung, Helen E. Vuong, Cristopher D. G. Luna, Geoffrey N. Pronovost, Antoniya A. Aleksandrova, Noah G. Riley, Anastasia Vavilina, Julianne McGinn, Tomiko Rendon, Lucy R. Forrest, Elaine Y. Hsiao
NATURE MICROBIOLOGY
(2019)
Article
Biology
Wenchang Zhou, Giacomo Fiorin, Claudio Anselmi, Hossein Ali Karimi-Varzaneh, Horacio Poblete Section, Lucy R. Forrest, Jose D. Faraldo-Gomez
Article
Biology
Katherine E. Huffer, Antoniya A. Aleksandrova, Andres Jara-Oseguera, Lucy R. Forrest, Kenton J. Swartz
Article
Biochemistry & Molecular Biology
Wenchang Zhou, Gianluca Trinco, Dirk J. Slotboom, Lucy R. Forrest, Jose D. Faraldo-Gomez
Summary: This study explores the role of excitatory amino acid transporters (EAAT) in synaptic communication and the significance of a conserved methionine in the transport mechanism. By investigating the coordination of this methionine with Na+ ions, researchers have shed light on its impact on substrate turnover rate and specificity, providing insights into the ion-coupling mechanism of this class of transporters.
NEUROCHEMICAL RESEARCH
(2022)
Article
Multidisciplinary Sciences
Yuan-Wei Zhang, Stacy Uchendu, Vanessa Leone, Richard T. Bradshaw, Ntumba Sangwa, Lucy R. Forrest, Gary Rudnick
Summary: The study found that chloride ions, along with sodium ions and glycine, stabilize an inward-open conformation of the human GlyT1 transporter, providing an unexpected insight into the role of chloride in this transporter family.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Rene Staritzbichler, Edoardo Sarti, Emily Yaklich, Antoniya Aleksandrova, Marcus Stamm, Kamil Khafizov, Lucy R. Forrest
Summary: Aligning primary sequences is crucial in protein structure, function, and evolution analysis, but it is challenging for integral membrane proteins. Manual adjustments for optimum alignment can reduce robustness and reproducibility, while using anchors helps modify alignments without compromising their integrity.
Correction
Biochemistry & Molecular Biology
Wenchang Zhou, Gianluca Trinco, Dirk J. Slotboom, Lucy R. Forrest, Jose D. Faraldo-Gomez
NEUROCHEMICAL RESEARCH
(2022)
Article
Biophysics
Kyle C. Kihn, Tyree Wilson, Ally K. Smith, Richard T. Bradshaw, Patrick L. Wintrode, Lucy R. Forrest, Angela Wilks, Daniel J. Deredge
Summary: PhuS from Pseudomonas aeruginosa plays essential roles in heme uptake and iron homeostasis by shuttling heme to HemO for degradation and binding DNA to modulate the transcription of small RNAs. Heme binding to PhuS induces large conformational rearrangements, particularly in alpha-helices 6, 7, and 8, which are crucial for its functions. Computational methods are used to reveal the conformational landscape of apo-PhuS, providing structural insights into heme modulation of its dual function.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Rene Staritzbichler, Emily Yaklich, Edoardo Sarti, Nikola Ristic, Peter W. Hildebrand, Lucy R. Forrest
Summary: The AlignMe web server is a valuable resource for aligning membrane protein sequences, and recent improvements in anchoring, multiple submissions, and structure visualization have enhanced its functionality.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biophysics
Vanessa Leone, Richard T. Bradshaw, Caroline Koshy, Paul Suhwan Lee, Cristina Fenollar-Ferrer, Veronika Heinz, Christine Ziegler, Lucy R. Forrest
Summary: Membrane transporters are essential for cellular function by mediating the passage of molecules across membranes. The cytoplasmic regions of these proteins are required for modulating their activity, but obtaining atomic-resolution descriptions of these regions can be challenging. This study focuses on BetP, a membrane protein whose autoregulation depends on its cytoplasmic segments, and uses molecular simulations to investigate the structure and dynamics of these segments. The results provide insights into the molecular mechanism of autoregulation and reveal an intricate interplay between the three protomers of BetP.
BIOPHYSICAL JOURNAL
(2023)
Article
Multidisciplinary Sciences
Giacomo Fiorin, Lucy R. Forrest, Jose D. Faraldo-Gomez
Summary: All lipid membranes have inherent morphological preferences and resist deformation. The effects of cholesterol on bending rigidity are lipid-specific and arise from differences in the torsional dynamics of the acyl chains. Enhanced-sampling all-atom molecular dynamics simulations allow for the direct quantification of both bending and tilt moduli and provide insights into the contributing factors and molecular mechanisms of curvature generation at each length scale.