Article
Multidisciplinary Sciences
Jie Yu, Prashant Rao, Sarah Clark, Jaba Mitra, Taekjip Ha, Eric Gouaux
Summary: AMPA receptors play a crucial role in mediating signal transduction in the hippocampal neuronal circuits, and their function is regulated by auxiliary protein subunits that associate with the receptors in a specific manner. Different combinations of AMPA receptor auxiliary subunits may have diverse impacts on the receptor function.
Article
Biology
Yang Dong, Jiali Wang, Rachel-Ann Garibsingh, Keino Hutchinson, Yueyue Shi, Gilad Eisenberg, Xiaozhen Yu, Avner Schlessinger, Christof Grewer, Randy B. Stockbridge
Summary: EAAT1 is a glutamate transporter that regulates extracellular glutamate concentration in the brain, while ASCT2 is an amino acid transporter involved in the movement of glutamine between intracellular and extracellular compartments. Both transporters belong to the SLC1 family and share a similar mechanism of allosteric modulation, as discovered through experimental and computational studies.
Article
Chemistry, Medicinal
Yue Pan, Mary M. Mader
Summary: This article introduces allosteric inhibition of kinases, summarizes the discovery of allosteric MEK1/2 and BCR-ABL1 inhibitors, and discusses the approaches to screening and validating allosteric inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Anika J. Friedman, Evan T. Liechty, Levi Kramer, Ankur Sarkar, Jerome M. Fox, Michael R. Shirts
Summary: Protein tyrosine phosphatases (PTPs) are potential drug targets for various diseases, but the design of selective therapeutics is complicated. This study investigates the allosteric inhibition of PTP1B by AD, an unusually selective inhibitor. Molecular dynamics simulations suggest that AD stably interacts with the allosterically influential region of PTP1B. The binding requires a disordered alpha 7 helix, contributing to the selectivity of AD. The findings indicate the potential of AD as a scaffold for building allosteric inhibitors of PTP1B.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Biochemistry & Molecular Biology
Ma Yangchun, Yang Wenyu, Zhou Liang, Li Lipeng, Wu Jingwei, Li Weiya, Du Shan, Ma Ying, Wang Runling
Summary: Studies have shown that the dual allosteric targeted inhibition mechanism of SHP2 involves the combination of SHP099 and SHP844 to inhibit the pharmacological pathway in cells and prevent the substrate from entering the catalytic site.
MOLECULAR DIVERSITY
(2022)
Review
Biochemistry & Molecular Biology
Beatrice Balboni, Mirco Masi, Walter Rocchia, Stefania Girotto, Andrea Cavalli
Summary: Most kinase inhibitors target ATP-binding sites, resulting in promiscuity and potential off-target effects. Allostery provides an alternative approach to achieve selectivity, but its exploitation is challenging due to diverse mechanisms and long-range conformational effects. GSK-3 beta, a critical target involved in multiple pathologies, shares a highly homologous ATP-binding site with other kinases. Allostery offers the potential for selective and moderate inhibition, which is desirable for GSK-3 beta. However, the development of allosteric inhibitors for GSK-3 beta has been limited, with only one reaching clinical trials, and there are no X-ray structures of GSK-3 beta with allosteric inhibitors in the PDB data bank.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Sunzhenhe Fang, Xiaowei Huang, Xue Zhang, Minhua Zhang, Yahui Hao, Hui Guo, Lu-Ning Liu, Fang Yu, Peng Zhang
Summary: The study presents the three-dimensional structures of the cyanobacterial Synechocystis sp. PCC 6803 SbtA-SbtB complex, revealing the functional unit as a trimer and the elevator mechanism adopted by SbtA for bicarbonate transport. The allosteric inhibition of SbtA by SbtB mainly occurs through the T-loop of SbtB, stabilizing the conformation with AMP molecules binding at the trimer interfaces. This unique regulatory mechanism of SbtA by SbtB highlights the importance of studying inorganic carbon uptake systems in CCM for potential modification of crop photosynthesis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Arek Melkonian, Elise Loppinet, Renata Martin, Matthew Porteus, Chaitan Khosla
Summary: Extracellular TG2 activity is competitively controlled by high-affinity Ca2+ ion binding and strained disulfide bond formation, leading to either enzyme protection or complete inactivation. Minor changes in redox catalysts or promoters in the extracellular matrix can significantly alter steady-state TG2 activity. TG2 serves as a molecular OR gate determining its catalytic fate upon export from cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Justin M. Di Trani, Agnes Moe, Daniel Riepl, Patricia Saura, Ville R. Kaila, Peter Brzezinski, John L. Rubinstein
Summary: The mitochondrial electron transport chain plays a critical role in ATP synthesis, and CIV, the terminal oxidase, transfers electrons from cytochrome c to oxygen. This study shows that steroids can inhibit CIV activity by binding to a specific site and modulating the conformational dynamics and proton transfer kinetics within the K pathway. Understanding this regulatory mechanism sheds light on the respiratory regulation and provides insights into the structural gating mechanisms in the CIV catalytic cycle.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Leah G. Helton, Ahmed Soliman, Felix von Zweydorf, Michalis Kentros, Jascha T. Manschwetus, Scotty Hall, Bernd Gilsbach, Franz Y. Ho, Panagiotis S. Athanasopoulos, Ranjan K. Singh, Timothy J. LeClair, Wim Versees, Francesco Raimondi, Friedrich W. Herberg, Christian Johannes Gloeckner, Hardy Rideout, Arjan Kortholt, Eileen J. Kennedy
Summary: Dimerization of LRRK2 can be inhibited by specific constrained peptides, leading to decreased kinase activity, reduced ROS production, and inhibition of PD-related apoptosis in primary cortical neurons. Unlike other inhibitors, these peptides do not affect the cellular localization of LRRK2.
ACS CHEMICAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Rishi K. Vishwakarma, M. Zuhaib Qayyum, Paul Babitzke, Katsuhiko S. Murakami
Summary: NusG is a transcription elongation factor that induces transcription pausing in bacteria by interacting with a specific sequence in the non-template DNA strand. The interaction between NusG and the DNA rearranges the transcription bubble and affects the conformational changes of RNA polymerase, leading to the inhibition of RNA synthesis. This mechanism of pausing is widely conserved in bacteria.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Peter G. Miller, Murugappan Sathappa, Jamie A. Moroco, Wei Jiang, Yue Qian, Sumaiya Iqbal, Qi Guo, Andrew O. Giacomelli, Subrata Shaw, Camille Vernier, Besnik Bajrami, Xiaoping Yang, Cerise Raffier, Adam S. Sperling, Christopher J. Gibson, Josephine Kahn, Cyrus Jin, Matthew Ranaghan, Alisha Caliman, Merissa Brousseau, Eric S. Fischer, Robert Lintner, Federica Piccioni, Arthur J. Campbell, David E. Root, Colin W. Garvie, Benjamin L. Ebert
Summary: This study elucidates the molecular mechanism of GSK2830371 activity by using computational, biochemical and functional genetic studies. The data shows that GSK2830371 binds to an allosteric site of PPM1D with high affinity and shifts the equilibrium to the inactive form. Additionally, it is found that C-terminal truncating mutations destabilize the protein. These findings provide insights into the biology of PPM1D.
NATURE COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Lisa M. Hochrein, Heyun Li, Niles A. Pierce
Summary: The activity of conditional guide RNA (cgRNA) is dependent on the presence of an RNA trigger, enabling cell-selective regulation of CRISPR/Cas function. Allosteric cgRNA mechanisms allow independent design of target and trigger sequences, providing flexibility to select regulatory targets and scope independently. The high-performance allosteric cgRNAs demonstrated for ON -> OFF and OFF -> ON logic in mammalian cells lay the foundation for programmable cell-selective regulation applications.
ACS SYNTHETIC BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Victoria R. Mingione, YiTing Paung, Ian R. Outhwaite, Markus A. Seeliger
Summary: The human genome contains over 500 different protein kinases that have tightly regulated activity as signaling enzymes. The enzymatic activity of the conserved kinase domain is influenced by various regulatory inputs, including the binding of regulatory domains, substrates, and post-translational modifications such as autophosphorylation. This review focuses on the allosteric regulation of protein kinases and highlights recent advances in this field.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Chemistry, Multidisciplinary
Xuan Tao, Lu Zhang, Liubing Du, Ruyan Liao, Huiling Cai, Kai Lu, Zhennan Zhao, Yanxuan Xie, Pei-Hui Wang, Ji-An Pan, Yuebin Zhang, Guohui Li, Jun Dai, Zong-Wan Mao, Wei Xia
Summary: The study demonstrates that colloidal bismuth subcitrate is an effective inhibitor of SARS-CoV-2 3CLpro, leading to proteolytic dysfunction by binding to an allosteric site.
Article
Chemistry, Multidisciplinary
Elena Shanina, Sakonwan Kuhaudomlarp, Kanhaya Lal, Peter H. Seeberger, Anne Imberty, Christoph Rademacher
Summary: Carbohydrate-binding proteins, specifically lectins, are promising targets in drug discovery for combating antimicrobial resistance, yet non-carbohydrate drug-like inhibitors are still lacking. A druggable pocket in a beta-propeller lectin from Burkholderia ambifaria has been identified as a potential target for allosteric inhibitors. Future drug-discovery efforts focusing on small molecule inhibitors could benefit from targeting allosteric sites in lectins to combat antibiotic-resistant pathogens.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biochemistry & Molecular Biology
Eike Siebs, Elena Shanina, Sakonwan Kuhaudomlarp, Priscila da Silva Figueiredo Celestino Gomes, Cloe Fortin, Peter H. Seeberger, Didier Rognan, Christoph Rademacher, Anne Imberty, Alexander Titz
Summary: This study reports a new approach to inhibit the formation of Pseudomonas aeruginosa biofilms. By synthesizing galactosidic LecA inhibitors with aromatic moieties targeting the central pocket, the formation of biofilms was successfully reduced.
Article
Biochemistry & Molecular Biology
Wen-Ting Lo, Hassane Belabed, Murat Kuecuekdisli, Juliane Metag, Yvette Roske, Polina Prokofeva, Yohei Ohashi, Andre Horatscheck, Davide Cirillo, Michael Krauss, Christopher Schmied, Martin Neuenschwander, Jens Peter von Kries, Guillaume Medard, Bernhard Kuster, Olga Perisic, Roger L. Williams, Oliver Daumke, Bernard Payrastre, Sonia Severin, Marc Nazare, Volker Haucke
Summary: In this study, we developed a novel PI3KC2 alpha catalytic activity inhibitor PITCOIN, which exhibits strong selectivity towards PI3KC2 alpha due to its unique mode of interaction with the ATP-binding site of the enzyme. It was demonstrated that PITCOINs can inhibit the PI3KC2 alpha-mediated synthesis of phosphatidylinositol 3-phosphates, impairing endocytic membrane dynamics and platelet-dependent thrombus formation.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Paula Samso, Philipp A. Koch, York Posor, Wen-Ting Lo, Hassane Belabed, Marc Nazare, Jocelyn Laporte, Volker Haucke
Summary: X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies. This study shows that defective focal adhesions and reduced active beta-integrin surface levels in XLCNM can be rescued by loss of PI3KC2 beta function. The researchers also demonstrate the unknown role of PI3KC2 beta in the endocytic trafficking of active beta 1-integrins, providing a potential treatment option for XLCNM patients.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Physical
Tobias Sprenger, Thomas Schwarze, Holger Mueller, Eric Sperlich, Alexandra Kelling, Hans-Juergen Holdt, Jerome Paul, Vera Martos Riano, Marc Nazare
Summary: In this study, fluorescent probes for the selective quantification of Na+ and K+ in water were developed. These probes showed stability over a wide range of pH values and were not affected by other biologically relevant cations.
Article
Multidisciplinary Sciences
Philipp Jordan, Amanda Costa, Edgar Specker, Oliver Popp, Andrea Volkamer, Regina Piske, Tessa Obrusnik, Sabrina Kleissle, Kevin Stuke, Andre Rex, Martin Neuenschwander, Jens Peter von Kries, Marc Nazare, Phillip Mertins, Helmut Kettenmann, Susanne A. Wolf
Summary: Microglia, as the immune effector cells of the CNS, respond to pathologic events by releasing nitric oxide (NO). A compound called C1 was found to significantly reduce NO release in a dose-dependent manner, with a low IC50 (252 nM), and no toxic effects in vitro or in vivo. Target finding strategies, such as in silico modelling and mass spectroscopy, suggest a direct interaction between C1 and nitric oxide synthase, making C1 a promising candidate for specific intra-cellular interaction with the NO producing machinery.
Article
Biology
Felix F. Fuchsberger, Dongyoon Kim, Natalia Baranova, Hanka Vrban, Marten Kagelmacher, Robert Wawrzinek, Christoph Rademacher
Summary: Glycan-binding proteins called lectins are important for translating glycans into biochemical signals in mammalian cells. Studying their signaling capacity and integration is crucial for understanding immune cell function. This study focused on C-type lectin receptors and found that most receptors transmit information similarly, except for dectin-2. Furthermore, the integration of multiple signal transduction pathways, including synergistic lectins, was explored to understand how immune cells translate glycan information using multivalent interactions.
Review
Pharmacology & Pharmacy
Davide Cirillo, Marta Diceglie, Marc Nazare
Summary: Phosphoinositide-3-kinases (PI3Ks) play a central role in various cellular signaling pathways and are potential targets for pharmacological treatment of diseases such as cancer, thrombosis, and pulmonary diseases. Isoform-selective inhibitors have been developed and approved, but challenges regarding drug tolerance have been observed. Therefore, additional approaches are needed, including targeting underexplored PI3K class II isoforms, to enhance the clinical benefits of specific treatment options. This review highlights recent discoveries in isoform-selective inhibitors, with a focus on PI3K class II isoforms, and emphasizes the importance of developing a broader arsenal of pharmacological tools.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Medicine, Research & Experimental
Ludger Starke, Jason M. Millward, Christian Prinz, Fatima Sherazi, Helmar Waiczies, Christoph Lippert, Marc Nazare, Friedemann Paul, Thoralf Niendorf, Sonia Waiczies
Summary: The study demonstrates that siponimod can be imaged non-invasively using 19F UTE MRI, laying the foundation for further preclinical and clinical investigations. This technique provides an accurate understanding of the distribution of CNS-acting drugs in individual patients, which can contribute to personalized therapy.
Meeting Abstract
Oncology
Paul Curtis Schope, Shixian Yan, Dennis Kobelt, Joe Lewis, Kerstin Putzker, Ulrike Uhrig, Edgar Specker, Jens Peter von Kries, Mathias Dahlmann, Hector E. Sanchez-Ibarra, Anke Unger, Mia-Lisa Zischinsky, Bert Klebl, Peter Lindemann, Wolfgang Walther, Marc Nazare, Ulrike Stein
Article
Chemistry, Medicinal
Maria Isabel Fernandez-Bachiller, Songhwan Hwang, Maria Elena Schembri, Peter Lindemann, Monica Guberman, Svenja Herziger, Edgar Specker, Hans Matter, David W. Will, Jorg Czech, Michael Wagner, Armin Bauer, Herman Schreuder, Kurt Ritter, Matthias Urmann, Volkmar Wehner, Han Sun, Marc Nazare
Summary: The study examined two series of factor Xa ligands through experimental and computational approaches, identifying new ligands with higher affinity and demonstrating the terminal alkyne moiety as a suitable non-classical bioisosteric replacement for higher halogen-pi aryl interactions.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Clinical Neurology
Jacqueline Langedijk, Erika Ivanna Araya, Amanda Ribeiro Barroso, Dagmar Tolenaars, Marc Nazare, Hassane Belabed, Jens Schoene, Juliana Geremias Chichorro, Ronald Oude Elferink
Summary: This study investigates the effects of the LPAR5 antagonist cpd3 on pain and itch signaling. The results show that cpd3 can reduce nociceptive behavior but induces scratching in mice. In vitro experiments reveal that cpd3 can activate TRPA1 to inhibit intracellular calcium release. However, this effect is not observed in TRPA1-deficient mice. These findings highlight the importance of screening antinociceptive drugs for their activity with pruriceptors.
FRONTIERS IN PAIN RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Monica Guberman, Miroslav Kosar, Anahid Omran, Erick M. Carreira, Marc Nazare, Uwe Grether
Summary: Labeled chemical probes are crucial for the development and commercialization of drugs. They play a significant role in various research phases and provide valuable tools for specific application needs. The reverse-design approach enables the generation of high-quality probes based on previously optimized small molecules, fostering collaborations between academia and industry.
Article
Biochemistry & Molecular Biology
Hengxi Zhang, Carlos Modenutti, Yelha Phani Kumar Nekkanti, Maxime Denis, Iris A. Bermejo, Jonathan Lefebre, Kateryna Che, Dongyoon Kim, Marten Kagelmacher, Dennis Kurzbach, Marc Nazare, Christoph Rademacher
Summary: This study investigated the exact binding site of human and murine homologues of Langerin using structural comparison and molecular dynamics simulations. It was found that the nonconserved short loops exhibited a high degree of conformational flexibility between the two homologues. Sequence analysis and mutational studies identified a pair of residues essential for recognizing thiazolopyrimidines. By utilizing solvent paramagnetic relaxation enhancement NMR studies and a series of peptides, the allosteric binding site for these aromatic heterocycles was determined to be the cleft between the short and long loops.
ACS CHEMICAL BIOLOGY
(2022)
Article
Nanoscience & Nanotechnology
Chandradhish Ghosh, Patricia Priegue, Harin Leelayuwapan, Felix F. Fuchsberger, Christoph Rademacher, Peter H. Seeberger
Summary: This study reports that glyconanoparticles decorated with nonimmunogenic oligosaccharides can activate innate immune response without significantly affecting the complement system.
ACS APPLIED BIO MATERIALS
(2022)