Review
Cell Biology
Shuya Kate Huang, R. Scott Prosser
Summary: This review highlights the recent progress in understanding the structural dynamics of G protein-coupled receptors (GPCRs) using techniques such as nuclear magnetic resonance (NMR) and spectroscopy. It reveals that GPCRs and their signaling complexes are dynamic allosteric systems that exhibit multiple functional states under normal conditions. The distribution of these states and their transitions are regulated by ligands, allosteric modulators, and the membrane environment. This ensemble view of GPCRs provides insights into pharmacological phenomena associated with receptor signaling.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Albert A. Smith, Emelyne M. Pacull, Sabrina Stecher, Peter W. Hildebrand, Alexander Vogel, Daniel Huster
Summary: G protein-coupled receptors initiate signal transduction by binding with ligands. In this study, we focus on the growth hormone secretagogue receptor (GHSR), which binds with the 28 residue peptide ghrelin. We compared the dynamics of apo and ghrelin-bound GHSR using long molecular dynamics simulation trajectories and identified differences in dynamics in specific regions. We also investigated the traversal of GHSR over a rugged energy landscape via principal component analysis.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Biochemistry & Molecular Biology
T. Reid Alderson, Lewis E. Kay
Summary: The article demonstrates the importance of nuclear magnetic resonance (NMR) spectroscopy in studying the dynamic structures of biomolecules, including its wide range of applications in revealing biomolecular motions, functional dynamics in large molecular machines, transient conformations implicated in disease onset, and weak interactions involved in liquid-liquid phase separation.
Article
Biochemistry & Molecular Biology
Daniela Roversi, Cassandra Troiano, Evgeniy Salnikov, Lorenzo Giordano, Francesco Riccitelli, Marta De Zotti, Bruno Casciaro, Maria Rosa Loffredo, Yoonkyung Park, Fernando Formaggio, Maria Luisa Mangoni, Burkhard Bechinger, Lorenzo Stella
Summary: Antimicrobial peptides (AMPs) are a promising class of compounds for fighting resistant infections. They kill bacteria by disrupting the permeability of their cell membranes. However, the accumulation of peptides on bacterial membranes can also interfere with vital cellular functions by perturbing bilayer dynamics, a phenomenon known as "sand in the gearbox".
BIOPHYSICAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Udeep Chawla, Suchithranga M. D. C. Perera, Steven D. E. Fried, Anna R. Eitel, Blake Mertz, Nipuna Weerasinghe, Michael C. Pitman, Andrey V. Struts, Michael F. Brown
Summary: Visual rhodopsin absorbs light and takes in approximately 80 water molecules to form a solvent-swollen active state, which is essential for activating the photoreceptor and is supported by molecular dynamics simulations. Force-based measurements show that the expansion of rhodopsin occurs through changes in cavity volumes and increased hydration in the active Meta II state. Furthermore, the binding and release of the C-terminal helix of transducin is coupled to hydration changes, potentially influencing visual signal amplification through a dynamic allosteric mechanism involving lipid and water interactions in the catalytic G-protein cycle.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Jan H. Overbeck, Jennifer Vogele, Felix Nussbaumer, Elke Duchardt-Ferner, Christoph Kreutz, Jens Wohnert, Remco Sprangers
Summary: The synthetic neomycin-sensing riboswitch interacts with neomycin, ribostamycin, and paromomycin. However, only neomycin can efficiently repress translation initiation due to differences in ligand:riboswitch dynamics. Five complementary fluorine-based NMR methods were used to accurately quantify dynamics in the riboswitch complexes and identified four structurally different states. These findings highlight the potential of F-19 NMR methods in characterizing complex exchange processes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Morgane Adelaide, Evgeniy Salnikov, Francisco Ramos-Martin, Christopher Aisenbrey, Catherine Sarazin, Burkhard Bechinger, Nicola D'Amelio
Summary: SAAP-148 is an antimicrobial peptide derived from LL-37 with excellent activity against drug-resistant bacteria and biofilms. Its mechanism of action at the molecular level has not been explored despite its optimal pharmacological properties.
Article
Multidisciplinary Sciences
Alexandre Pozza, Francois Giraud, Quentin Cece, Marina Casiraghi, Elodie Point, Marjorie Damian, Christel Le Bon, Karine Moncoq, Jean-Louis Baneres, Ewen Lescop, Laurent J. Catoire
Summary: This study provides a detailed description of the close relationships between membrane proteins and lipids using lipid nanodiscs and high-pressure NMR. The results show a link between pressure and lipid compositions to the conformational landscape of the membrane proteins. The study also reveals that pressure can modify the conformation and gelation of lipids, and that membrane proteins can modulate the fluidity of the bilayer.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Rongfu Zhang, Timothy A. Cross, Xinhua Peng, Riqiang Fu
Summary: Understanding the dynamics and structure of water is crucial in biological systems. Directly probing the interfacial water in hydrated phospholipids is challenging, but a novel solid-state NMR technique was developed to successfully observe two distinct water species in the headgroup region of hydrated lipid bilayers. These findings provide an opportunity to study water dynamics on a millisecond or slower timescale in biomacromolecules.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Zhong Wang, Hannah R. Felstead, Robert I. Troup, Bruno Linclau, Philip T. F. Williamson
Summary: Bioactive compounds require crossing membranes to reach their site of action. The octanol-water partition coefficient (logP(OW)) serves as a reliable proxy for membrane permeability. In drug discovery, both logP(OW) and bioactivity are optimized together, and fluorination is one of the relevant strategies. This study examined the correlation between logP(OW) values and membrane molar partitioning coefficients (logK(p)) using lipid vesicles and found that factors affecting logP modifications also affect membrane permeability.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Huy N. Hoang, Timothy A. Hill, David P. Fairlie
Summary: Research has shown that a single methyl group only increases membrane permeability when it connects or expands hydrophobic surface patches. Positional isomers with the same characteristics can have different permeabilities based on the size of the largest continuous hydrophobic surface patch, illuminating a key local molecular determinant of membrane permeability.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Multidisciplinary Sciences
Junlin Wang, Richard D. Ye
Summary: The bacteria-derived formyl peptide fMet-Leu-Phe (fMLF) can activate different cellular functions at different concentrations, promoting migration at subnanomolar concentrations and bactericidal activities at higher concentrations. The mechanism of concentration-dependent signaling in FPR1 agonist has been discovered.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Alida Besch, William M. Marsiglia, Moosa Mohammadi, Yingkai Zhang, Nathaniel J. Traaseth
Summary: Many human cancers are treated with small molecule inhibitors that target the kinase domain of receptor tyrosine kinases. Long-term treatment often leads to drug resistance mutations at the gatekeeper residue, increasing the aggressiveness of the cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Siddharth Sinha, Benjamin Tam, San Ming Wang
Summary: Molecular Dynamics (MD) Simulations is a powerful tool used for studying protein structure-related questions. It has been widely applied to research protein function, stability, interactions, and more.
Article
Biochemistry & Molecular Biology
Hongyi Wu, Ruiyu Cao, Shukun Wei, Salma Pathan-Chhatbar, Maorong Wen, Bin Wu, Wolfgang W. Schamel, Shuqing Wang, Bo OuYang
Summary: Research reveals that cholesterol and cholesterol sulfate affect the conformation and clustering of TCR, with the atomic interaction mechanism being highlighted. The results validate the binding sites of cholesterol and CS with TCR.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Florian J. Gisdon, Josef P. Kynast, Merve Ayyildiz, Anna V. Hine, Andreas Pluckthun, Birte Hoecker
Summary: Current biomedical research and diagnostics rely heavily on detection agents for specific identification and quantification of protein molecules. Commercial reagent antibodies, however, lack specificity or fail to recognize their target. Hence, there is a need for synthetic alternatives developed through multidisciplinary approaches integrating experimental protein engineering with computational modeling.
BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Mariam Mohamadi, David Goricanec, Gerhard Wagner, Franz Hagn
Summary: G protein-coupled receptors (GPCRs) are important drug targets and the high-resolution structures of GPCRs have provided great insights. However, understanding the dynamic nature of GPCRs is equally important and can be obtained by NMR spectroscopy. In this study, the NMR sample optimization of the neurotensin receptor type 1 (NTR1) variant HTGH4 was performed using size exclusion chromatography, thermal stability measurements, and 2D-NMR experiments. The short-chain lipid DH7PC was identified as a promising membrane mimetic for high-resolution NMR experiments. NMR and hydrogen deuterium exchange (HDX) mass spectrometry experiments were used to probe structural changes at the ligand binding site in different functional states.
JOURNAL OF STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Umut Guensel, Kai Kloepfer, Elisabeth Haeusler, Manuel Hitzenberger, Bettina Boelter, Laura E. Sperl, Martin Zacharias, Juergen Soll, Franz Hagn
Summary: Triose phosphates (TPs) are exported from chloroplasts into the cytosol across the inner and outer envelope membranes. The mode of action of transporters in the outer envelope remains unclear. The structure of the outer envelope protein 21 (OEP21) from garden pea was determined, revealing its cone-shaped beta-barrel structure and positively charged interior that facilitates binding and translocation of metabolites. The channel is stabilized by ATP and may provide a means of controlling metabolite transport across the outer envelope.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jie Shi, Kristine Hauschulte, Ivan Mikicic, Srijana Maharjan, Valerie Arz, Tina Strauch, Jan B. Heidelberger, Jonas Schaefer, Birgit Dreier, Andreas Plueckthun, Petra Beli, Helle D. Ulrich, Hans-Peter Wollscheid
Summary: The study investigates the role of actin and associated molecules in the nucleus, focusing on the actin-based motor myosin VI in protecting stalled replication forks. The actin cytoskeleton is important for cellular structure and plasticity, but the abundance and function of filamentous actin in the nucleus are still debated.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Christoph Klenk, Maria Scrivens, Anina Niederer, Shuying Shi, Loretta Mueller, Elaine Gersz, Maurice Zauderer, Ernest S. Smith, Ralf Strohner, Andreas Pluckthun
Summary: The authors developed a method to alter the biophysical and functional properties of G protein-coupled receptors through directed evolution in mammalian cells. They evolved neurotensin receptor 1 for high stability and expression and demonstrated that receptors with complex molecular architectures and large ligands can also be evolved. Importantly, their approach allows for the evolution of functional receptor properties in the presence of the mammalian signaling environment, resulting in receptor variants with increased allosteric coupling.
NATURE COMMUNICATIONS
(2023)
Article
Microbiology
Marine Blanc, Clara Lettl, Jeremy Guerin, Anais Vieille, Sven Furler, Sylvie Briand-Schumacher, Birgit Dreier, Celia Berge, Andreas Pluckthun, Sandrine Vadon-Le Goff, Remi Fronzes, Patricia Rousselle, Wolfgang Fischer, Laurent Terradot
Summary: The study focuses on Helicobacter pylori, a bacterial pathogen that injects the oncoprotein CagA into gastric cells using a type IV secretion system (cagT4SS). The research shows that CagI, a protein present on the surface of the bacterium, is crucial for the formation of the pilus that facilitates CagA delivery. DARPins targeting CagI are identified as potent inhibitors of the cagT4SS, which is a major risk factor for gastric cancer development.
Article
Biology
Rajib Schubert, Taegeun Bae, Branko Simic, Sheena N. Smith, Seong-Ho Park, Gabriela Nagy-Davidescu, Viviana Gradinaru, Andreas Pluckthun, Junho K. Hur
Summary: Tissue clearing combined with deep imaging is a powerful tool for expanding classical histological techniques. However, imaging highly melanin-rich tissues remains challenging. To address this, researchers developed a CRISPR-based gene editing method called CRISPR-Clear, which can be incorporated into existing tissue-clearing workflows. The method was successfully applied to melanoma tumors, allowing detailed characterization through staining and imaging techniques.
COMMUNICATIONS BIOLOGY
(2023)
Article
Radiology, Nuclear Medicine & Medical Imaging
Ruben D. Houvast, Nada Badr, Taryn March, Lysanne D. A. N. de Muynck, Vincent Q. Sier, Timo Schomann, Shadhvi Bhairosingh, Victor M. Baart, Judith A. H. M. Peeters, Gerard J. P. van Westen, Andreas Plueckthun, Jacobus Burggraaf, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Cornelis F. M. Sier
Summary: This study evaluated the preclinical potential of EpCAM-binding DARPins for NIRF and PA imaging of cancer, demonstrating clear tumor delineation in vivo.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2023)
Article
Biochemistry & Molecular Biology
Sarah Klinnert, Corinne D. Schenkel, Patrick C. Freitag, Huldrych F. Guenthard, Andreas Plueckthun, Karin J. Metzner
Summary: This study uses gene therapy to target and eliminate cells infected with HIV-1 by activating latent virus and killing the cells. This targeted gene therapy approach has the potential to effectively and safely eliminate infected cells.
Article
Immunology
Liridona Maliqi, Nikolas Friedrich, Matthias Glogl, Stefan Schmutz, Daniel Schmidt, Peter Rusert, Merle Schanz, Maryam Zaheri, Chloe Pasin, Cyrille Niklaus, Caio Foulkes, Thomas Reinberg, Birgit Dreier, Irene Abela, David Peterhoff, Alexandra Hauser, Roger D. Kouyos, Huldrych F. Guenthard, Marit J. van Gils, Rogier W. Sanders, Ralf Wagner, Andreas Plueckthun, Alexandra Trkola
Summary: Understanding the balance between epitope shielding and accessibility on HIV-1 envelope trimers is crucial for selecting immunogens for bnAb-based vaccines. This study introduces a strategy using synthetic DARPin libraries to investigate the antigenic properties of Env immunogens. The in vitro screening tool, DANA, can provide relevant information of antigenic features of Env immunogens. The findings demonstrate that stronger trimer stabilization leads to the selection of highly mutated DARPins, mirroring observations made for bnAbs. By mimicking immunization regimens, DANA can be used to select immunogen combinations that favor trimer-reactive binders.
Article
Biochemistry & Molecular Biology
Melanie Gut, Birgit Dreier, Sven Furler, Jens Sobek, Andreas Pluckthun, Jason P. Holland
Summary: Late-stage prostate cancer often becomes resistant to standard chemotherapy and transforms into a hormone-resistant, drug-resistant, and incurable disease. Developing non-invasive tools to detect biochemical changes that indicate drug efficacy and identify drug resistance could have significant implications in managing individual patients' treatment plans. In this study, new Designed Ankyrin Repeat Proteins (DARPins) with high affinity for prostate-specific antigen (PSA) were selected using ribosome display and in vitro screening tools. These PSAbinding DARPins showed nanomolar affinity for PSA and could be radiolabeled for potential use in imaging-based monitoring of androgen receptor (AR)-targeted therapies.
RSC CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Christian Baumann, Wan-Chin Chiang, Renato Valsecchi, Simon Jurt, Mattia Deluigi, Matthias Schuster, Karl Johan Rosengren, Andreas Pluckthun, Oliver Zerbe
Summary: This study investigates the rapid side-chain dynamics of an alpha(1B)-adrenergic receptor using methyl relaxation. The results show that the overall side-chain dynamics of the receptor are similar in the presence of different ligands. However, the allosteric ligand increases the flexibility of certain key residues, suggesting differences in the mechanisms for receptor activation. These findings demonstrate the feasibility of studying receptor-wide side-chain dynamics in GPCRs to gain functional insights.
Meeting Abstract
Biotechnology & Applied Microbiology
Sebastian Schellhorn, Dominik Bruecher, Natascha A. Wolff, Katrin Schroeer, Erwan Sallard, Kemal Mese, Wenli Zhang, Eric Ehrke-Schulz, Frank Thevenod, Andreas Plueckthun, Anja Ehrhardt
Meeting Abstract
Biotechnology & Applied Microbiology
K. P. Hartmann, M. Van Gogh, G. Nagy-Davidescu, P. C. Freitag, A. Plueckthun
HUMAN GENE THERAPY
(2022)
Meeting Abstract
Pharmacology & Pharmacy
C. Klenk, A. Niederer, M. Scrivens, E. Smith, M. Zauderer, A. Plueckthun
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
(2022)