Article
Biochemistry & Molecular Biology
Ryan J. Shirey, Jonathan R. Hart, BanuPriya Sridharan, Scott J. Novick, Lewis D. Turner, Bin Zhou, Alexander L. Nielsen, Lisa M. Eubanks, Lynn Ueno, Mark S. Hixon, Luke L. Lairson, Timothy P. Spicer, Louis D. Scampavia, Patrick R. Griffin, Peter K. Vogt, Kim D. Janda
Summary: A fluorescent small molecule probe was discovered to detect the oncoprotein MYC, leading to the development of a high-throughput screening assay for MYC inhibitor scaffolds. Screening resulted in molecules with better drug-like properties, with one specific lead showing potent inhibition of oncogenic transformation.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Analytical
Joseph Anacleto, Cristina Lento, Vladimir Sarpe, Ayesha Maqsood, Banafsheh Mehrazma, David Schriemer, Derek J. Wilson
Summary: Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a rapidly growing technique that provides information about the dynamic structural changes in proteins during biological function. The continuous flow injection setup for time-resolved HDX-MS (CFI-TRESI-HDX) introduced in this work allows for automated, continuous or discrete labeling time measurements from milliseconds to hours, with substantially reduced runtimes compared to conventional systems.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Analytical
Eric Largy, Matthieu Ranz
Summary: Hydrogen-deuterium exchange mass spectrometry (HDX/MS) is used for studying protein conformation dynamics and characterizing oligonucleotide conformations and their interactions with cations, small molecules, and proteins. OligoR is a web-based application that provides dedicated solutions for processing and visualizing native HDX/MS data of oligonucleotides. It offers a simple and robust approach to deconvoluting bimodal isotope distributions and can be extended to various analytes. The results are presented in interactive data tables and can be exported as publication-quality figures.
ANALYTICAL CHEMISTRY
(2023)
Article
Chemistry, Analytical
Ramin Ekhteiari Salmas, Antoni James Borysik
Summary: The quantification of hydrogen deuterium exchange (HDX) kinetics provides information on the stability of individual amino acids in proteins. The new programming tool HDXmodeller allows for optimization of low-resolution HDX-mass spectrometry (MS) data to understand exchange rates of individual amino acids. The tool also has a unique autovalidation method based on a covariance matrix for quantifying the accuracy of modeled exchange rates.
ANALYTICAL CHEMISTRY
(2021)
Editorial Material
Biochemistry & Molecular Biology
Jianjun Duan, David G. Lambright
Summary: The article explores the structural basis for Sar1 activation by the Sec12 guanine nucleotide exchange factor during COPII vesicle biogenesis at the endoplasmic reticulum.
Article
Chemistry, Analytical
Josiah J. Rensner, Young Jin Lee
Summary: This study developed a highly efficient hydrogen-deuterium exchange technique for more accurate metabolite identification in MALDI-MS imaging, while retaining spatial information. By combining deuterium-labeled matrix and D2O vapor, an HDX efficiency of 73-85% was achieved. This method can systematically improve untargeted metabolite annotation through METASPACE annotation.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemical Research Methods
Yoshitomo Hamuro, Stephen J. Coales
Summary: This note discusses the challenges and considerations of observing perturbation of a protein upon binding to a ligand with weak affinity using HDX-MS. The theoretical analysis suggests that the ratio of ligand concentration to dissociation constant can greatly impact the results of the experiment.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2022)
Article
Chemistry, Analytical
Jiarong Wang, Bo Wu, Youjia Zhang, Liang Ge, Junfeng Wang
Summary: In this study, a 1D F-19 NMR-based method was developed for rapid detection of GEF activity of sGTPases, by tracking the conformational changes of the Arf6 switch region. This strategy could potentially be applied to monitor the conformational change of Arf6 or other sGTPase and detect the activities of sGTPase regulatory proteins in physiology and pathology environments.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jarrod J. Sandow, Iris Kl Tan, Alan S. Huang, Shashank Masaldan, Jonathan P. Bernardini, Ahmad Z. Wardak, Richard W. Birkinshaw, Robert L. Ninnis, Ziyan Liu, Destiny Dalseno, Daisy Lio, Giuseppi Infusini, Peter E. Czabotar, Andrew Webb, Grant Dewson
Summary: In this study, the dynamic structural mechanisms of BAK activation on a membrane were explored using HDX-MS. It was found that the BH4 domain maintains the inactive conformation of BAK, and the N-terminal region becomes disordered post-activation without affecting its membrane permeabilization. These findings provide new insights into the potential therapeutic targeting opportunities for BAK activation.
Article
Engineering, Environmental
Hang Liu, Hongyang Cui, Yixuan Huang, Yi Yang, Ling Jiao, Yulan Zhou, Jianying Hu, Yi Wan
Summary: Environmental pollutants can disrupt the homeostasis of endogenous metabolites in organisms. Enzymes can catalyze hydrogen-deuterium (H-D) exchange and be used to screen for critical biological molecules affected by environmental pollutants. This research provides a tool for discovering more molecular targets of metabolic disruptors.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Article
Chemistry, Applied
Hannah J. Mckerchar, Cristina Lento, Rachel Z. Bennie, Jennifer M. Crowther, Fabian Dolamore, Jolon M. Dyer, Stefan Clerens, Davide Mercadante, Derek J. Wilson, Renwick C. J. Dobson
Summary: The properties of milk proteins vary between different mammalian species. This study focuses on comparing the dynamics of beta-lactoglobulin (β lg) proteins from goat and cow milk at different pH levels. The dimeric states of the cow β lg B variant homologue exhibit more conformational flexibility than the goat β lg at lower pH, as observed through hydrogen/deuterium exchange experiments and molecular dynamics simulations. Understanding these dynamic differences in β lg homologues is crucial for understanding the variations in milk processing, human digestion, and immunogenicity.
Article
Biochemistry & Molecular Biology
Edward A. Dennis
Summary: Lipids play important roles in chronic diseases, but defining the substrate specificity of lipid metabolism enzymes is challenging. This research focuses on how membranes interact with enzymes to regulate cell signaling and metabolic pathways. By using substrate lipidomics and molecular dynamics simulations, the study reveals the link between enzyme specificity and hydrophobic binding subsites for membrane phospholipid substrates.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Materials Science, Paper & Wood
Yan Song, Wei Jiang, Haoxi Ben, Yuanming Zhang, Guangting Han, Arthur J. Ragauskas
Summary: Preparation of deuterium incorporated cellulose is important for investigating cellulose internal structure and expanding its application fields. The study successfully prepared cellulosic cotton fibers with anti-rehydration deuterium incorporation and characterized the process using nuclear magnetic resonance and spectroscopy. The results showed that the hydrogen-deuterium exchange occurred preferentially in the amorphous cellulose component and increased treatment time led to higher deuterium incorporation. Additionally, the isotope effect did not affect the cellulose microstructure, crystalline index, or degree of polymerization properties significantly.
Article
Biochemical Research Methods
Yoshitomo Hamuro
Summary: In order to make a quantitative argument for a hydrogen/deuterium exchange-mass spectrometry (HDX-MS) experiment, optimization at different stages and extraction of relevant values from medium-resolution data is necessary, while being cautious of potential false results.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2021)
Article
Biochemical Research Methods
Bradley B. Stocks, Gregory H. Bird, Loren D. Walensky, Jeremy E. Melanson
Summary: The number of approved peptide therapeutics and those in development is increasing. The biological activity of therapeutic peptides is often influenced by their structural elements, with stabilizing features improving bioavailability. The use of hydrocarbon stapling can dramatically stabilize alpha-helical peptides. Mass spectrometry techniques like IM and HDX can detect multiple peptide conformations, aiding in the identification of optimally stapled peptides.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2021)
Article
Multidisciplinary Sciences
Hua Liu, Fang C. Mei, Wenli Yang, Hui Wang, Eitan Wong, Jingjing Cai, Emma Toth, Pei Luo, Yue-Ming Li, Wenbo Zhang, Xiaodong Cheng
Article
Endocrinology & Metabolism
Han Xie, Natesh Yepuri, Qinghe Meng, Ravi Dhawan, Colin A. Leech, Oleg G. Chepurny, George G. Holz, Robert N. Cooney
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
(2020)
Article
Chemistry, Medicinal
Brandon T. Milliken, Clinton Elfers, Oleg G. Chepurny, Kylie S. Chichura, Ian R. Sweet, Tito Borner, Matthew R. Hayes, Bart C. De Jonghe, George G. Holz, Christian L. Roth, Robert P. Doyle
Summary: This study developed a novel peptide, GEP44, targeting GLP-1R and Y2-R, which showed greater reduction in body weight compared to Ex-4 without triggering nausea, offering a promising route for new glucoregulatory treatments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Ian C. Tinsley, Tito Borner, MacKenzie L. Swanson, Oleg G. Chepurny, Sarah A. Doebley, Varun Kamat, Ian R. Sweet, George G. Holz, Matthew R. Hayes, Bart C. De Jonghe, Robert P. Doyle
Summary: Corrination involves conjugating a corrin ring-containing molecule with molecules, peptides, or proteins to modify pharmacology. By optimizing the lead conjugate for GLP-1R agonism and binding, an improved GLP-1R agonist with reduced penetration into the central nervous system and devoid of anorexia and emesis has been developed.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Endocrinology & Metabolism
Wenqin Xu, Sam P. Dahlke, Andrew C. Emery, Michelle Sung, Oleg G. Chepurny, George G. Holz, Lee E. Eiden
Summary: In NS-1 neuroendocrine cells, PACAP activates the Rap-Braf-MEK-ERK pathway via the G(s)-protein coupled receptor PAC1 to promote neuritogenesis. VIPR1/2 and GLP1R agonists did not induce neuritogenesis or cAMP elevation, potentially due to insufficient receptor protein expression.
JOURNAL OF NEUROENDOCRINOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hossam R. Elgiushy, Nageh A. Abou-Taleb, George G. Holz, Oleg G. Chepurny, Ioannis Pirmettis, Sotirios Kakabakos, Vlasios Karageorgos, George Liapakis, Amgad Albohy, Khaled A. M. Abouzid, Sherif F. Hammad
Summary: Novel thiazolo[4,5-d]pyrimidine derivatives have been identified as potential candidates for treating depression and anxiety by targeting the CRFR1 receptor. Compound 8c showed the highest binding affinity and inhibitory effect on CRF induced cAMP accumulation, suggesting its potential as a therapeutic agent. Docking and molecular dynamics simulations indicated a similar allosteric binding mode for 8c compared to the known cocrystalized ligand CP-376395 in the 4K5Y pdb file.
BIOORGANIC CHEMISTRY
(2021)
Article
Cell Biology
Zhuofu Ni, Xiaodong Cheng
Summary: EPAC proteins are only present in multicellular Metazoa, with EPAC1 only associated with chordates and EPAC2 spanning the entire animal kingdom. EPAC1 has undergone more selection and evolved faster than EPAC2.
Article
Biochemistry & Molecular Biology
Nshunge Musheshe, Asmaa Oun, Angelica Maria Sabogal-Guaqueta, Marina Trombetta-Lima, Sarah C. Mitchel, Ahmed Adzemovic, Oliver Speek, Francesca Morra, Christina H. J. T. van der Veen, Frank Lezoualc'h, Xiaodong Cheng, Martina Schmidt, Amalia M. Dolga
Summary: By modulating the activity of Epac proteins in neuronal cells, the study showed that Epac1 inhibition can prevent cell death and loss of mitochondrial integrity induced by ferroptosis, while Epac2 inhibition has limited effects. This suggests that Epac1 may be a potential therapeutic target for preventing ferroptosis cell death associated with neurodegenerative diseases.
Article
Endocrinology & Metabolism
Qinghe Meng, Oleg G. Chepurny, Colin A. Leech, Napat Pruekprasert, Megan E. Molnar, James Jason Collier, Robert N. Cooney, George G. Holz
Summary: This study investigated the blood glucose-lowering effects of the alpha-7 nicotinic acetylcholine receptor (alpha 7nAChR) agonist GTS-21 in db/db mice and the requirement for alpha 7nAChR and GLP-1 receptor (GLP-1R) stimulation. The results showed that GTS-21 improved oral glucose tolerance in db/db mice through coordinated alpha 7nAChR and GLP-1R stimulation. These findings suggest that combining alpha 7nAChR agonists with sitagliptin may be a potential new treatment for type 2 diabetes.
DIABETES OBESITY & METABOLISM
(2022)
Article
Multidisciplinary Sciences
Wenli Yang, William G. Robichaux, Fang C. Mei, Wei Lin, Li Li, Sheng Pan, Mark A. White, Yuan Chen, Xiaodong Cheng
Summary: It has been found that cAMP regulates cellular SUMOylation through Epac1, which also controls the dynamics of cellular condensates. This research provides insights into the molecular mechanism linking cellular stress responses and protein SUMOylation.
Editorial Material
Biochemistry & Molecular Biology
Xiaodong Cheng
Summary: Protein SUMOylation is an essential post-translational modification for maintaining cellular homeostasis. Recent evidence suggests that liquid-liquid phase separation (LLPS)/ biomolecular condensates play a role in regulating cellular SUMOylation, providing insights into its cellular mechanism.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Xiaodong Cheng, Wenli Yang, Wei Lin, Fang Mei
Summary: This review summarizes recent progress in understanding the mechanisms of SUMO regulation, focusing on the potential roles of liquid-liquid phase separation/biomolecular condensates in regulating cellular SUMOylation during cellular stresses. Additionally, the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation are discussed.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Multidisciplinary Sciences
Kylie S. Chichura, Clinton T. Elfers, Therese S. Salameh, Varun Kamat, Oleg G. Chepurny, Aelish McGivney, Brandon T. Milliken, George G. Holz, Sarah V. Applebey, Matthew R. Hayes, Ian R. Sweet, Christian L. Roth, Robert P. Doyle
Summary: Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery involve changes in gut hormone levels, including GLP-1 and PYY. It has been demonstrated that two peptide biased agonists of GLP-1, Y1-R, and Y2-R receptors (GEP44 and GEP12) can stimulate insulin secretion and glucose uptake, as well as reduce food intake and body weight. These findings suggest the therapeutic potential of targeting multiple receptors for long-term benefits in patients.
SCIENTIFIC REPORTS
(2023)
Article
Medicine, Research & Experimental
Viktor N. Tomilin, Kyrylo Pyrshev, Anna Stavniichuk, Naghmeh Hassanzadeh Khayyat, Guohui Ren, Oleg Zaika, Sherif Khedr, Alexander Staruschenko, Fang C. Mei, Xiaodong Cheng, Oleh Pochynyuk
Summary: Epac1 and Epac2 have similar but nonredundant roles in renal sodium handling. Inhibition of Epac signaling could be instrumental in the treatment of hypertensive states associated with ENaC overactivation.
Article
Biology
Brandon T. Milliken, Oleg P. Chepurny, Robert G. Doyle, George G. Holz