Article
Biochemistry & Molecular Biology
Benjamin Friedman, Ane Larranaga-Vera, Cristina M. Castro, Carmen Corciulo, Piul Rabbani, Bruce N. Cronstein
Summary: The pathogenesis of osteoarthritis (OA) is related to imbalanced chondrocyte homeostasis and increased cellular senescence in cartilage. Activation of adenosine A2A receptor (A2AR) promotes cartilage regeneration and chondrocyte homeostasis. A2AR activation reduces chondrocyte senescence and attenuates OA progression.
Article
Chemistry, Multidisciplinary
Daniel. L. L. Gao, Malkiat. S. S. Johal
Summary: Cardiovascular disease (CVD), the leading cause of mortality in the United States, is primarily caused by atherosclerosis characterized by fibrofatty plaque formation. Fibrinogen, an important clotting factor, plays a role in promoting atherogenesis through various mechanisms. However, impaired clearance mechanisms during atherosclerosis indicate the defective efferocytosis. This study identified fibrinogen as a ligand of LRP-1 and characterized its binding, providing insights into the probable cause of defective efferocytosis in atherosclerosis.
Article
Pharmacology & Pharmacy
Luke J. Hamilton, Michaela Walker, Mahesh Pattabiraman, Haizhen A. Zhong, Brandon Luedtke, Surabhi Chandra
Summary: The study generated a novel isomer of curcumin using photochemical methods and found that this compound binds to two receptor subtypes with K-i values of 5μM and 7μM, respectively. The results showed that this isomer is non-toxic to cells and may potentially be developed as a new class of non-opioid analgesics.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Michal Zaluski, Dorota Lazewska, Piotr Jasko, Ewelina Honkisz-Orzechowska, Kamil J. Kuder, Andreas Brockmann, Gniewomir Latacz, Malgorzata Zygmunt, Maria Kaleta, Beril Anita Greser, Agnieszka Olejarz-Maciej, Magdalena Jastrzebska-Wiesek, Christin Vielmuth, Christa E. Mueller, Katarzyna Kiec-Kononowicz
Summary: This study synthesized 25 novel xanthine derivatives with potential anti-inflammatory activity and explored their effects on neurodegenerative diseases such as Parkinson's disease. Three compounds were selected for further studies and showed good metabolic stability and anti-inflammatory activity in vitro and in vivo. Further optimization of these compounds and exploration of their therapeutic potential in neurodegenerative diseases are warranted.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Akihisa Mori, Brittany Cross, Shinichi Uchida, Jill Kerrick Walker, Robert Ristuccia
Summary: Adenosine is widely distributed in the central and peripheral nervous systems as a key neuromodulator, with implications in the pathogenesis of neurodegenerative disorders, especially in ALS. Motor neurons affected in ALS are responsive to adenosine receptor function, with accumulating evidence supporting the benefits of adenosine A(2A) receptor antagonism.
Article
Biochemistry & Molecular Biology
Hector Godoy-Marin, Romain Duroux, Kenneth A. Jacobson, Concepcio Soler, Hildegard Colino-Lage, Veronica Jimenez-Sabado, Jose Montiel, Leif Hove-Madsen, Francisco Ciruela
Summary: Atrial fibrillation (AF) is influenced by various factors such as oxidative stress, calcium overload, inflammation, as well as adenosine and its receptors. Studies have found increased A2AR expression in the right atrium of AF patients, elevated levels of adenosine content in plasma, and reduced ADA activity. Importantly, there is a positive correlation between A2AR expression in PBMCs and in the right atrium.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Sofia Beghi, Malgorzata Furmanik, Armand Jaminon, Rogier Veltrop, Nikolas Rapp, Kanin Wichapong, Elham Bidar, Annamaria Buschini, Leon J. Schurgers
Summary: Cardiovascular disease remains a major cause of death worldwide, despite advancements in medication and preventive measures. Calcium plays a vital role in the cardiovascular system, regulating events from action potentials to muscle contraction. Calcium calmodulin pathways are involved in the regulation of cardiac functions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Michal Marcinkowski, Tomas Pilzys, Damian Garbicz, Jan Piwowarski, Kaja Przygonska, Maria Winiewska-Szajewska, Karolina Ferenc, Oleksandr Skorobogatov, Jaroslaw Poznanski, Elzbieta Grzesiuk
Summary: FTO is an N-6-methyladenosine demethylase which can remove methyl groups from nucleic acids, forming complexes with other proteins. Research indicates an interaction between FTO and calmodulin (CaM), influencing calcium-binding loops in CaM.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Raphael Bolteau, Romain Duroux, Amelie Laversin, Brandon Vreulz, Anna Shiriaeva, Benjamin Stauch, Gye Won Han, Vadim Cherezov, Nicolas Renault, Amelie Barczyk, Severine Ravez, Mathilde Coevoet, Patricia Melnyk, Maxime Liberelle, Said Yous
Summary: The past fifty years have seen an increase in the prevalence of neurodegenerative diseases, but current treatments only provide symptomatic relief, leading to the need for new therapeutic targets. This paper focuses on the adenosine A2A receptor (A2AAR) as a potential target, reporting the design, synthesis, and pharmacological analysis of quinazoline derivatives as high-efficiency A2AAR antagonists. Through virtual screening, a series of 2-aminoquinazoline compounds were identified, with one compound (21a, Ki= 20 nM) showing promising affinity towards A2AAR. This ligand was crystallized in complex with A2AAR, confirming predicted docking poses and opening up opportunities for further optimization to develop selective ligands for specific adenosine receptor subtypes.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
P. Boknik, J. Eskandar, B. Hofmann, N. Zimmermann, J. Neumann, U. Gergs
Summary: This review provides an overview of the localization and role of cardiac A(2A)-adenosine receptors, as well as their potential involvement in relevant cardiac pathologies. The review also discusses the cardiac utility of A(2A)-AR as therapeutic targets and identifies gaps in knowledge for future research.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hung N. Do, Sana Akhter, Yinglong Miao
Summary: Caffeine is a common antagonist to adenosine GPCRs and its binding mechanism to the A(2A)AR was studied using GaMD simulations, revealing characteristic hydrogen bonding and an intermediate binding conformation. The sequence-divergent ECL2 region of the A(2A)AR may be an attractive target site for designing selective allosteric modulators.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Cell Biology
Tharaka Wijerathne, Wei -Yin Lin, Akila Cooray, Shmuel Muallem, Kyu Pil Lee
Summary: Recent structural studies have found that the carboxyl-terminus of TRP channels, including TRPC3, is folded into a horizontal rib helix connected to a vertical pole helix, which plays a role in interactions and multimerization. By identifying key hydrophobic residues in the pole helix and using mutations, the study determines their role in TRPC3 regulation by Ca2+ and Calmodulin. The findings suggest that the hydrophobic starch formed by these residues modulates TRPC3 gating, channel selectivity, and Ca2+ permeability.
Article
Biology
Shuya Kate Huang, Omar Almurad, Reizel J. Pejana, Zachary A. Morrison, Aditya Pandey, Louis-Philippe Picard, Mark Nitz, Adnan Sljoka, R. Scott Prosser
Summary: Cholesterol indirectly modulates the conformational equilibria and signaling of the adenosine A(2A) receptor by influencing membrane properties.
Article
Biochemistry & Molecular Biology
Samantha L. Cooper, Edward S. Wragg, Patrizia Pannucci, Mark Soave, Stephen J. Hill, Jeanette Woolard
Summary: This study investigates the regional selectivity of A(2A) and A(2B) receptors in regulating vascular tone in the rat cardiovascular system. The results show that A(2A)-selective agonists increase heart rate and hindquarters vascular conductance, while A(2B)-selective agonists increase heart rate and vascular conductance in the renal and mesenteric vascular beds. These findings provide insights into the function and vascular regulatory mechanisms of adenosine receptors, and suggest a potential therapeutic approach for acute kidney injury.
Review
Biochemistry & Molecular Biology
Catia Lambertucci, Gabriella Marucci, Daniela Catarzi, Vittoria Colotta, Beatrice Francucci, Andrea Spinaci, Flavia Varano, Rosaria Volpini
Summary: Endogenous nucleoside adenosine, particularly the A(2A) subtype, plays an important role in the treatment of neurodegenerative disorders involving neuroinflammation. Inhibition of A(2A) adenosine receptors exhibits neuroprotective effects and counteracts neuroinflammatory processes. The approval of A(2A) adenosine receptor antagonist istradefylline opens up new therapeutic opportunities for these diseases.
CURRENT MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Vebjorn Martinsen, Petri Kursula
Summary: MBP is an abundant protein in CNS myelin and is studied in relation to the pathogenesis of MS. While its direct role as a primary antigen in human MS is unclear, MBP and its functions in myelin formation and maintenance are linked to the disease. This molecule demonstrates the complex relationship between normal nervous system development and neurodegenerative disease.
Article
Biochemistry & Molecular Biology
Abris Adam Bendes, Petri Kursula, Inari Kursula
Summary: Apicomplexan parasites rely on the glideosome for motility and host cell invasion; actin filament capping proteins (CPs) play a crucial role in regulating actin dynamics; this study presents the crystal structure of CP from the malaria parasite and reveals differences compared to canonical heterodimers.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Correction
Cell Biology
Arne Raasakka, Petri Kursula
Article
Biochemistry & Molecular Biology
Laura Kind, Arne Raasakka, Janne Molnes, Ingvild Aukrust, Lise Bjorkhaug, Pal Rasmus Njolstad, Petri Kursula, Thomas Arnesen
Summary: In this study, the structure and function of HNF-1A were analyzed, and several pathogenic variants related to MODY3 were identified. These findings are important for precise diagnosis and treatment of diabetes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Correction
Biochemistry & Molecular Biology
Yuta Ishizuka, Tadiwos F. Mergiya, Rodolfo Baldinotti, Ju Xu, Erik I. Hallin, Sigurbjorn Markusson, Petri Kursula, Clive R. Bramham
NEUROCHEMICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Yuta Ishizuka, Tadiwos F. Mergiya, Rodolfo Baldinotti, Ju Xu, Erik Hallin, Sigurbjorn Markusson, Petri Kursula, Clive R. Bramham
Summary: Arc protein plays important roles in synaptic plasticity, memory, and cognitive flexibility. This study developed anti-Arc nanobodies as new tools to investigate Arc dynamics and function, and found that ArcNbs have versatile applications.
NEUROCHEMICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Aleksi Sutinen, Giang Thi Tuyet Nguyen, Arne Raasakka, Gopinath Muruganandam, Remy Loris, Emil Ylikallio, Henna Tyynismaa, Luca Bartesaghi, Salla Ruskamo, Petri Kursula
Summary: This study investigates the biochemical and structural properties of GDAP1 gene mutations causing Charcot-Marie-Tooth disease. The findings reveal that these mutations lead to alterations in GDAP1 structure and decreased thermal stability, resulting in insufficient neuronal function.
Correction
Biochemistry & Molecular Biology
Giang Thi Tuyet Nguyen, Aleksi Sutinen, Arne Raasakka, Gopinath Muruganandam, Remy Loris, Petri Kursula
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Salla Ruskamo, Arne Raasakka, Jan Skov Pedersen, Anne Martel, Karel Skubnik, Tamim Darwish, Lionel Porcar, Petri Kursula
Summary: This study characterized the three-dimensional structure and functional differences of the most abundant protein in myelin, PLP, and its isoform DM20, and revealed the mechanisms of their interactions with lipids. Reconstituted PLP and DM20 spontaneously induced the formation of multi-layered membrane structures similar to myelin in the lipid bilayers. These findings contribute to a better understanding of the organization and function of proteins in compact myelin in the central nervous system.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Multidisciplinary Sciences
Sigurbjorn Markusson, Erik Hallin, Helene J. Bustad, Arne Raasakka, Ju Xu, Gopinath Muruganandam, Remy Loris, Aurora Martinez, Clive R. Bramham, Petri Kursula
Summary: Activity-regulated cytoskeleton-associated protein (Arc) plays a vital role in synaptic plasticity and memory formation. This study used high-affinity anti-Arc nanobodies to investigate the structure and function of Arc. The results suggest that the N-terminal domain of Arc is involved in membrane binding, while the C-terminal domain binds to postsynaptic protein ligands. Furthermore, the NTD and CTD are important for Arc oligomerisation and assembly of capsids.
Article
Genetics & Heredity
Mirella Vinci, Petri Kursula, Donatella Greco, Maurizio Elia, Luigi Vetri, Carmelo Schepis, Valeria Chiavetta, Serena Donadio, Michele Roccella, Marco Carotenuto, Valentino Romano, Francesco Cali
Summary: This study reports a case of CFC-like phenotype in a patient with compound heterozygote missense mutations in the AHNAK2 gene. The mutations were found to be unrelated to known genes associated with CFC syndrome, and their impact on protein function was predicted to be not severe. The mutations were located in flexible regions possibly involved in molecular interactions.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Sigurbjorn Markusson, Jens G. Hjorleifsson, Petri Kursula, Bjarni Asgeirsson
Summary: This study reveals the presence of two chloride binding sites in the structure of marine bacterial alkaline phosphatase (VAP), one in the active site and another at a peripheral site. Binding of chloride ions to the peripheral site decreases structural dynamics, leading to thermal stabilization of the VAP active conformation. The binding of chloride ion in the active site does not displace the bound inorganic phosphate product, but it may promote product release by facilitating rotational stabilization of the substrate-binding Arg129.
Article
Multidisciplinary Sciences
Aleksi Sutinen, Dirk Paffenholz, Giang Thi Tuyet Nguyen, Salla Ruskamo, Andrew E. Torda, Petri Kursula
Summary: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its subtypes are linked to mutations in dozens of different genes, including the gene coding for ganglioside-induced differentiation-associated protein 1 (GDAP1). The etiology of GDAP1-linked CMT is poorly understood at the protein level, despite implications for mitochondrial fission and fusion, cytoskeletal interactions, and response to reactive oxygen species. Structural and biophysical analyses on several CMT-linked GDAP1 protein variants have been carried out, and new crystal structures of these variants have been described.
Article
Biochemistry & Molecular Biology
Dorothee Houry, Arne Raasakka, Eugenio Ferrario, Marc Niere, Ersilia Bifulco, Petri Kursula, Mathias Ziegler
Summary: In this study, the mechanism of increased substrate affinity of phosphorylated NAMPT is revealed, which includes the coordination of Mg2+ by phospho-His247 to stabilize PRPP in a position favorable for catalysis. Additionally, a stretch of 10 amino acids found only in NAMPTs from deuterostomes is shown to enhance conformational plasticity and stabilize the chemically unstable phosphorylation of His247. Overall, this study provides a structural basis for the important function of NAMPT in recycling Nicotinamide into NAD biosynthesis with high affinity.
JOURNAL OF STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Oda C. Krokengen, Arne Raasakka, Petri Kursula
Summary: Numerous human proteins, known as intrinsically disordered proteins (IDPs), lack high-resolution structural information due to their physicochemical properties. However, IDPs can adopt local ordered structures upon interaction with other proteins or lipid membranes. Using AlphaFold2 predictions and experimental data, we have found that the predicted models of two myelin-specific IDPs closely match their membrane-binding sites. These artificial intelligence-based models provide insight into the ligand-bound state of IDPs and are crucial for understanding the role of IDPs in diseases.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2023)