Article
Biochemistry & Molecular Biology
Cheng Zhong, Minze Xu, Senguel Boral, Holger Summer, Falk-Bach Lichtenberger, Cem Erdogan, Maik Gollasch, Stefan Golz, Pontus B. Persson, Johanna Schleifenbaum, Andreas Patzak, Pratik H. Khedkar
Summary: Aging affects the downstream signaling of the endothelial nitric oxide system in vascular smooth muscle, leading to compromised vasorelaxation even in the absence of histopathological alterations. The reduced expression of sGC and PDE5 may contribute to the impaired vasorelaxation in aged vessels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Kevin M. Gayler, Jeremy M. Quintana, Jordan Mattke, Michael A. Plunk, Jessica H. Kostyo, Johann W. Karunananthan, Harold Nguyen, Mina Shuda, Liam D. Ferreira, Hannah Baker, Alexandra L. Stinchcomb, Iraida Sharina, Robert R. Kane, Emil Martin
Summary: Previous studies have shown that the anti-hyperlipidemic drug gemfibrozil can activate the NO receptor soluble guanylyl cyclase independently of NO and heme. New gemfibrozil derivatives were synthesized and evaluated for sGC activation, identifying positions in gemfibrozil's structure that are important for activation. Compounds 7c and 15b were found to be more potent activators of purified sGC's cGMP-forming activity compared to gemfibrozil, showing enhanced relaxation of preconstricted mouse thoracic aorta rings. These findings provide insights for further optimization of sGC activators based on the gemfibrozil scaffold.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Miguel A. A. Olivencia, Leticia Gil de Biedma-Elduayen, Pablo Gimenez-Gomez, Bianca Barreira, Argentina Fernandez, Javier Angulo, Maria Isabel Colado, Esther O'Shea, Francisco Perez-Vizcaino
Summary: This study investigates the relationship between alcohol abuse and erectile dysfunction (ED), finding that alterations in soluble guanylyl cyclase (sGC) may contribute to ED caused by alcoholism. The results show that alcohol abuse reduces the relaxant response of the corpora cavernosa (CC) but enhances the response to sGC activators, while also increasing reactive oxygen species and protein expression of CYP2E1 and NOX2. These findings suggest that sGC activators may be effective in treating ED associated with alcoholism.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Cell Biology
Ayako Tonoki, Saki Nagai, Zhihua Yu, Tong Yue, Sizhe Lyu, Xue Hou, Kotomi Onuki, Kaho Yabana, Hiroki Takahashi, Motoyuki Itoh
Summary: This study identified the gyc beta gene as a negative regulator of age-related memory impairment (AMI) in fruit flies. It was shown that inhibition of the NO-sGC pathway enhanced intermediate-term memory (ITM) in aged individuals, suggesting a potential mechanism underlying memory impairment in aging.
Review
Pharmacology & Pharmacy
Wen Lu, Xiaoxiao Yang, Binghe Wang
Summary: The endogenous signaling roles of carbon monoxide (CO) have been established, but the molecular mechanism of how CO activates soluble guanylyl cyclase (sGC) is not clear. This review examines the discrepancies between the low affinity of sGC for CO and the reported activation, and suggests further studies to improve understanding of the CO-sGC axis.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Ellis Nelissen, Melissa Schepers, Laura Ponsaerts, Sebastien Foulquier, Annelies Bronckaers, Tim Vanmierlo, Peter Sandner, Jos Prickaerts
Summary: Vascular cognitive impairment (VCI) is a neurodegenerative disorder characterized by a vascular component, involving decreased cerebral blood flow, white matter lesions, endothelial dysfunction, and blood-brain barrier impairments. Oxidative stress and inflammation are major underlying mechanisms. Modulation of soluble guanylate cyclase (sGC) activity can improve vascular and neural function, and has shown efficacy in cardiovascular diseases.
PHARMACOLOGICAL RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Gang Wu, Iraida Sharina, Emil Martin
Summary: Nitric oxide (NO), carbon monoxide (CO), oxygen (O-2), and hydrogen sulfide (H2S) are gaseous molecules that play important roles in the physiology and pathophysiology of eukaryotes. Soluble guanylyl cyclase (sGC), a hemoprotein, acts as a sensor and transducer for these gases, as well as a transporter.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Construction & Building Technology
David W. Gardner, Jiaqi Li, Martin Kunz, Chenhui Zhu, Paulo J. M. Monteiro, Roya Maboudian, Carlo Carraro
Summary: The plastic deformation of C-(A-)S-H is relevant for Portland cement creep, with the strain in Si-O bonds not increasing when the material's silicate chains are cross-linked, and the silicate chains potentially being broken up when they are not cross-linked.
CEMENT AND CONCRETE RESEARCH
(2021)
Article
Neurosciences
Ellis Nelissen, Britt T. J. van Hagen, Elentina K. Argyrousi, Nick P. van Goethem, Pim R. A. Heckman, Dean Paes, Danielle A. J. Mulder-Jongen, Johannes G. Ramaekers, Arjan Blokland, Harald H. H. W. Schmidt, Jos Prickaerts
Summary: This study investigated the acute effects of riociguat, a soluble guanylate cyclase (sGC) stimulator, on memory function and neuronal plasticity in mice. The results showed that acute administration of low dose riociguat enhanced working memory, short-term memory, and long-term spatial memory. The memory-enhancing effects are likely regulated by peripheral effects on cyclic guanosine monophosphate (cGMP) signaling. However, further research is needed to explore the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance.
NEUROSCIENCE LETTERS
(2022)
Article
Urology & Nephrology
Rohit Patel, Yiling Fu, Ser Khang, Agnes M. Benardeau, Scott C. Thomson, Volker Vallon
Summary: sGC agonists have direct effects on kidney function and also impact it by reducing MAP. They tend to increase GFR directly, especially for MAP reductions <10%. However, when MAP declines further, the direct effect becomes subtle and overridden. The effects of sGC agonists on tubular reabsorption are mainly mediated by their effects on MAP.
Article
Biochemistry & Molecular Biology
Maryam Alapa, Chuanlong Cui, Ping Shu, Hong Li, Vlad Kholodovych, Annie Beuve
Summary: The study found that redox modifications play a crucial role in NO activation of GC1, with NO-stimulated GC1 containing more bound Cys, potentially disulfide bonds. Mass spectrometry identified ten oxidized and two reduced Cys in NO-stimulated GC1, and computational modeling narrowed down potential Cys candidates involved in disulfide bonds to Cys489 and Cys571. Mutational studies confirmed the involvement of Cys489 and Cys571 in GC1's response to NO, potentially as a thiol/disulfide switch.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Review
Cell Biology
Eric H. Mace, Melissa J. Kimlinger, Frederic T. Billings, Marcos G. Lopez
Summary: Ischemia and reperfusion (IR) damage organs and contribute to disease states. Augmenting nitric oxide (NO) signaling through soluble guanylyl cyclase (sGC) regulation shows promise as a therapeutic target. Preclinical studies have shown that sGC stimulators and activators can improve vasodilation and decrease IR injury in various organs. However, clinical trials of sGC activators have been terminated due to adverse side effects.
Article
Chemistry, Multidisciplinary
Jamal El Bakali, Michal Blaszczyk, Joanna C. Evans, Jennifer A. Boland, William J. McCarthy, Imam Fathoni, Marcio V. B. Dias, Eachan O. Johnson, Anthony G. Coyne, Valerie Mizrahi, Tom L. Blundell, Chris Abell, Christina Spry
Summary: By performing a fragment screen, we identified three series of fragments that occupy distinct regions in the active site of MtbPPAT. Guided by X-ray crystal structures, we successfully linked weakly-binding fragments to produce an active site binder with Mtb activity, as demonstrated by CRISPR interference. This study represents a significant progress in validating MtbPPAT as a potential drug target and designing anti-TB drugs targeting MtbPPAT.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Physiology
I. C. Wennysia, L. Zhao, T. Schomber, D. Braun, S. Golz, H. Summer, A. Benardeau, E. Y. Lai, F-B Lichtenberger, R. Schubert, P. B. Persson, M. Z. Xu, A. Patzak
Summary: The study suggests that the NO-sGC-cGMP system plays an important role in renal dilatation, with efferent arterioles having a stronger sGC activation dilatory system, while afferent arterioles are more sensitive to hypoxia/reoxygenation.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Anne Rehkamp, Dirk Tanzler, Christian Tuting, Panagiotis L. Kastritis, Claudio Iacobucci, Christian H. Ihling, Marc Kipping, Karl-Wilhelm Koch, Andrea Sinz
Summary: The study conducted a 3D-structural analysis of ROS-GC1 from bovine retina using cross-linking/mass spectrometry and computational modeling, revealing its active full-length structure and proposing a novel intracellular domain organization. The data supports a dimeric architecture of native ROS-GC1 from bovine retina and the integrated approach serves as a blueprint for conducting 3D-structural studies of membrane proteins in their native environment.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Sheng Zhang, Stan Yoo, Dalton T. Snyder, Benjamin B. Katz, Amy Henrickson, Borries Demeler, Vicki H. Wysocki, Adam G. Kreutzer, James S. Nowick
Summary: A beta dimers are neurotoxic and pathologically relevant species in Alzheimer's disease. This paper introduces a stable A beta(C18C33) dimer model that forms pure dimers in lipid environments without aggregation into fibrils. This model is important for amyloid and Alzheimer's disease research.
Review
Chemistry, Multidisciplinary
Dalton T. Snyder, Sophie R. Harvey, Vicki H. Wysocki
Summary: Native mass spectrometry (nMS) is an important tool in structural biology, with great potential due to a range of ionization techniques and new hybrid ion mobility and mass spectrometry systems. This review focuses on the key features and advantages of surface collisions (surface-induced dissociation, SID) for probing connectivity in protein and nucleoprotein complexes, demonstrating the importance of SID and nMS in future structural elucidation of biological assemblies.
Article
Biochemistry & Molecular Biology
Kye Stachowski, Andrew S. Norris, Devante Potter, Vicki H. Wysocki, Mark P. Foster
Summary: In this study, the mechanism of Cre recombinase assembly was revealed, which allows for DNA recognition and specific cleavage through a series of intermediates. The results show the importance of protein and DNA flexibility in site selection and recombination efficiency mediated by Cre.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Chemistry, Analytical
Justin T. Seffernick, S. M. Bargeen Ala m Turzo, Sophie R. . Harvey, Yongseok Kim, Arpad Somogyi, Shir Marciano, Vicki H. Wysocki, Steffen Lindert
Summary: Understanding the relationship between protein structure and experimental data is crucial. In this study, a method was developed to predict the full energy-resolved mass spectrometry (ERMS) plot from the structure. The results showed that the accuracy of predictions depended on the quality of the native crystal structures.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Remi Vuillemot, Alex Mirzaei, Mohamad Harastani, Ilyes Hamitouche, Leo Frechin, Bruno P. Klaholz, Osamu Miyashita, Florence Tama, Isabelle Rouiller, Slavica Jonic
Summary: This article presents a new method for extracting atomic-resolution landscapes of continuous conformational variability of biomolecular complexes from cryo-EM single particle images. The method, called MDSPACE, uses a 3D-to-2D flexible fitting method based on molecular dynamics simulation and is embedded in an iterative conformational-landscape refinement scheme. The article describes the MDSPACE approach and demonstrates its performance using synthetic and experimental datasets.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Editorial Material
Biochemical Research Methods
Vicki H. Wysocki
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Article
Biochemistry & Molecular Biology
Sravya Kovvali, Yuan Gao, Austin Cool, Steffen Lindert, Vicki H. Wysocki, Charles E. Bell, Venkat Gopalan
Summary: Amadori rearrangement products are stable sugar-amino acid conjugates that are formed nonenzymatically during food processing. Understanding bacterial utilization of these fructosamines is crucial due to their impact on the animal gut microbiome. In this study, the catalytic mechanism of the deglycase enzyme FrlB was elucidated through crystallography, computational docking, biochemical assays, and native mass spectrometry. The findings provide insights into the structure-function relationship and mechanisms of enzymes.
Article
Chemistry, Physical
Miki Nakano, Osamu Miyashita, Florence Tama
Summary: Single-particle analysis using x-ray free-electron lasers is a novel method for obtaining structural information of samples. This study evaluates the resolution of three-dimensional structures obtained from XFEL single-particle reconstruction using synthetic data. It is found that larger molecules can be restored with higher detail relative to their size, but achieving high absolute resolution is challenging.
STRUCTURAL DYNAMICS-US
(2023)
Article
Chemistry, Multidisciplinary
Thomas Walker, He Mirabel Sun, Tiffany Gunnels, Vicki Wysocki, Arthur Laganowsky, Hays Rye, David Russell
Summary: Variable-temperature electrospray ionization (vT-ESI) native mass spectrometry (nMS) is used to investigate the thermodynamics of ATP binding to the GroEL tetradecamer chaperonin complex. The study reveals strong enthalpy-entropy compensation (EEC) and variations in stepwise free energy changes, which are consistent with the established nested cooperativity model of GroEL-ATP interactions. The entropy-driven ATP binding is attributed to ligand-induced conformational changes and reorganization of water molecules within the GroEL complex.
ACS CENTRAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Osamu Miyashita, Florence Tama
Summary: Flexible fitting based on molecular dynamics simulation is a technique for structure modeling from cryo-EM data that has been used for nearly two decades. It provides a way to extract atomistic details of conformational changes encoded in cryo-EM data and improve the quality of structural models. Additionally, it enables the characterization of conformational heterogeneity in cryo-EM data. We will summarize the advancements made in these techniques and highlight recent developments in this field.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemical Research Methods
Mengxuan Jia, Yang Song, Chen Du, Vicki H. Wysocki
Summary: The charge partitioning during the dissociation of protein complexes in the gas phase is influenced by various factors, including interfacial interactions, protein flexibility, protein conformation, and dissociation methods. This study used two cysteine-containing homodimer proteins to investigate the charge partitioning behaviors of collision-induced dissociation (CID) and surface-induced dissociation (SID) processes. Results showed that restructuring dominates with CID, while dissociation with symmetric charge partitioning dominates with SID, regardless of the oxidation state of the intramolecular disulfide bonds. Gas collisions reveal the charge-dependent restructuring/unfolding properties of the protein precursor, while surface collisions predominantly lead to more charge-symmetric monomer separation.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Editorial Material
Biochemical Research Methods
Jenny Brodbelt, Vicki Wysocki
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Editorial Material
Biochemical Research Methods
John C. C. Tran, Iain D. G. Campuzano, Erin S. S. Baker, Vicki H. H. Wysocki
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Proceedings Paper
Computer Science, Interdisciplinary Applications
Paula Olaya, Silvina Caino-Lores, Vanessa Lama, Ria Patel, Ariel Keller Rorabaugh, Osamu Miyashita, Florence Tama, Michela Taufer
Summary: Capturing the structural information of biological molecules is crucial for understanding their function and mechanism. This research presents a framework, XPSI, which utilizes X-ray Free Electron Lasers to accurately predict the orientation, conformation, and protein type of molecules from their diffraction patterns. Compared to other machine learning methods, XPSI shows low computational cost and high prediction accuracy.
2022 IEEE 18TH INTERNATIONAL CONFERENCE ON E-SCIENCE (ESCIENCE 2022)
(2022)
Proceedings Paper
Computer Science, Interdisciplinary Applications
Ria Patel, Ariel Keller Rorabaugh, Paula Olaya, Silvina Caino-Lores, Georgia Channing, Catherine Schuman, Osamu Miyashita, Florence Tama, Michela Taufer
Summary: Neural networks are crucial for successful management of high-throughput scientific workflows. This study utilizes a multi-objective neural architecture search approach to generate accurate neural networks while optimizing for computational efficiency. By selecting and refining a subset of networks, efficient networks suitable for data analysis are obtained.
2022 IEEE 18TH INTERNATIONAL CONFERENCE ON E-SCIENCE (ESCIENCE 2022)
(2022)