Article
Pharmacology & Pharmacy
Ian H. H. Kimball, Phuong T. T. Nguyen, Baldomero M. M. Olivera, Jon T. T. Sack, Vladimir Yarov-Yarovoy
Summary: In this study, the interactions between mu-Conotoxin KIIIA and the human Na(V)1.7 channel were investigated using Rosetta computational modeling and in silico docking. The specific pairwise contacts between KIIIA and hNa(V)1.7 were predicted using RosettaDock and experimentally validated. Comparison with the cryo-EM structure of KIIIA-hNa(V)1.2 revealed important similarities and differences between Na-V channel subtypes, which may have implications for understanding the molecular mechanism of toxin block. The integrative approach used in this study suggests that Rosetta structural predictions can be useful for designing biologics targeting specific Na-V channels.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Guangsi Meng, Serdar Kuyucak
Summary: This study aims to improve the affinity and blocking capacity of mu-conotoxin KIIIA for Na(V)1.2 through computational studies. After molecular modeling and simulations on the Na(V)1.2-KIIIA complex, the S5R, S6D, and S13K mutations were identified as the most promising for additional contacts, which could enhance the affinity of KIIIA for Na(V)1.2 and enable complete blocking of the channel.
Article
Food Science & Technology
Kirsten L. McMahon, Hue N. T. Tran, Jennifer R. Deuis, David J. Craik, Irina Vetter, Christina Schroeder
Summary: mu-Conotoxins are peptide inhibitors of Na(V)1.7 channel with potential analgesic effects. Different mu-Conotoxins show varying selectivity towards hNa(V)1.7, with variations in loop 3 residue number and charged residues in this region affecting the selectivity. Additionally, the loop 1 extension in SxIIIC improves the inhibitory potency at hNa(V)1.7 compared to KIIIA.
Article
Biochemistry & Molecular Biology
Xunxun Jian, Yong Wu, Zaoli Mei, Xiaopeng Zhu, Dongting Zhangsun, Sulan Luo
Summary: In the synthesis of conotoxins with multiple disulfide bonds, determining the natural disulfide bond connectivities is challenging due to the diverse connectivities formed during oxidative folding. This study focuses on KIIIA, a mu-conotoxin with potent inhibitory activity against Nav1.2 and Nav1.4. The non-natural connectivity pattern of KIIIA exhibits the highest activity. The study optimized the Fmoc solid-phase synthesis of KIIIA using different strategies, finding that random oxidation and selective strategies can produce high yields and ideal isomers. Distributed oxidation with different protecting groups was also explored, indicating the importance of cleavage order for avoiding disulfide bond scrambling. The activity of synthesized isomers on Nav1.4 was tested, providing valuable guidance for future studies on multi-disulfide-bonded peptides.
Article
Biochemistry & Molecular Biology
Hue N. T. L. Tran, Kirsten R. McMahon, Jennifer Deuis, Irina I. Vetter, Christina Schroeder
Summary: This study evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of three isomers of mu-conotoxin KIIIA, and found that the disulfide bond structure affects the potency and subtype selectivity of mu-conotoxins targeting sodium channel subtypes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Zitong Zhao, Teng Pan, Shen Chen, Peta J. Harvey, Jinghui Zhang, Xiao Li, Mengke Yang, Linhong Huang, Shoushi Wang, David J. Craik, Tao Jiang, Rilei Yu
Summary: mu-Conotoxin KIIIA is a selective blocker of sodium channels with strong inhibitory activity against Nav1.7. Its structural modification and synthesis are challenging due to the presence of three pairs of disulfide bonds. In this study, three KIIIA analogues with one disulfide bond deleted were designed and synthesized. Among them, analogue KIIIA-1 showed the highest inhibitory activity on hNav1.7. A computational model was used to determine its binding pattern to hNav1.7 and guide the design of second and third-generation analogues. Peptide 37, the most potent analogue, exhibited significantly improved inhibitory activity on hNav1.7 and demonstrated potent analgesic effects in an in vivo pain model.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Angelica Ruelas-Callejas, Manuel B. Aguilar, Rogelio Arteaga-Tlecuitl, Juan Carlos Gomora, Estuardo Lopez-Vera
Summary: Conotoxin sr5a, a highly hydrophobic peptide, was found to selectively block the Na(V)1.5 subtype of sodium channels and modulate the voltage dependence of channel inactivation. This study reveals a potential new molecular interaction for sr5a and provides insights into its pharmacological activity.
Article
Multidisciplinary Sciences
Jian Huang, Xiao Fan, Xueqin Jin, Sooyeon Jo, Hanxiong Bear Zhang, Akie Fujita, Bruce P. Bean, Nieng Yan
Summary: Cannabidiol (CBD), a nonpsychoactive compound found in cannabis, is effective in treating epilepsy and pain. Researchers have discovered that CBD interacts with Na(v)1.7 channels at sub-micromolar concentrations, providing insights into its therapeutic mechanisms. The identification of binding sites for CBD may lead to the development of improved compounds for medical use.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Christopher Katnik, Javier Cuevas
Summary: The study focuses on intracellular ionic imbalance resulting from ischemic stroke, and the impact of NKCC1 antagonists on Na+ and Ca2+ overload. Loop diuretics BMN and EA inhibited ischemia-acidosis induced Ca2+ overload, but did not reduce Na+ increases.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Biology
Timothy J. Baumgartner, Zahra Haghighijoo, Nana A. Goode, Nolan M. Dvorak, Parsa Arman, Fernanda Laezza
Summary: Alzheimer's disease is characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta and intracellular hyperphosphorylated tau. Attenuation of hippocampal hyperactivity, which is linked to dysfunction of voltage-gated Na+ channels, has emerged as a promising therapeutic strategy for early-stage AD. This review explores the role of Nav channels in neuronal function, their connections to AD pathology, and their potential as therapeutic targets.
Review
Biochemistry & Molecular Biology
Silvia Cassinelli, Carla Vinola-Renart, Anna Benavente-Garcia, Maria Navarro-Perez, Jesusa Capera, Antonio Felipe
Summary: Protein lipidation is a common form of posttranslational modification that regulates various aspects of a protein's physiology, including its structure, stability, and interaction with cellular membranes. Palmitoylation, the addition of long saturated fatty acid chains to proteins, is a key form of lipidation. Enzymes called acyltransferases and thioesterases control the behavior of palmitoylated proteins through a series of acylation and deacylation cycles. Palmitoylation plays a pleiotropic role in regulating the trafficking, spatial organization, and electrophysiological properties of ion channels, particularly voltage-gated ion channels (VGICs). Dysregulation of palmitoylation in VGICs and associated subunits is linked to the development of diseases such as cancer and mental disorders. Therefore, protein palmitoylation is emerging as an important factor in cellular protein regulation and human health.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Shuang Ju, Yu Zhang, Xijun Guo, Qinghui Yan, Siyi Liu, Bokai Ma, Mei Zhang, Jiaolin Bao, Sulan Luo, Ying Fu
Summary: Conotoxins from marine cone snail venom are valuable drug resources and potential candidates for ovarian cancer treatment.
Review
Biochemistry & Molecular Biology
Xin Wu, Liang Hong
Summary: Calmodulin (CaM) is a small protein that serves as a ubiquitous signal transducer, regulating neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. Mutations in CaM-binding IQ domain can lead to various diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Gaoang Wang, Jiahui Yu, Hongyan Du, Chao Shen, Xujun Zhang, Yifei Liu, Yangyang Zhang, Dongsheng Cao, Peichen Pan, Tingjun Hou
Summary: As an important member of ion channels family, the voltage-gated sodium channel is associated with various diseases. Researchers have developed the first open-source database for voltage-gated sodium channels, providing comprehensive compound data for users to search and query.
JOURNAL OF CHEMINFORMATICS
(2022)
Article
Neurosciences
Victoria Gonzalez Sabater, Mark Rigby, Juan Burrone
Summary: In this study, the initiation and propagation of action potentials (APs) along the axon were investigated using genetically encoded voltage indicators (GEVIs) in dissociated hippocampal neurons from rat embryos. It was found that APs became sharper and exhibited greater fidelity as they traveled towards distal axonal domains. Blocking voltage-gated potassium channels (K-v) resulted in an increase in AP width, especially in distal locations, suggesting that higher levels of Kv channel activity in distal axons contribute to maintaining AP fidelity.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Biophysics
Fabian Giska, Malaiyalam Mariappan, Moitrayee Bhattacharyya, Kallol Gupta
Summary: In this study, the authors used native mass spectrometry (Native-MS) to investigate the oligomeric states and structural organization of the Get3/4/5 chaperone complex. They discovered that Get4/5 forms a tetramer and interacts with Get4/4 through a novel dimerization interface. Addition of Get3 results in the formation of a hexameric complex with a closed-ring cyclic architecture. These findings provide molecular-level insights and demonstrate the importance of native-MS in studying large multiprotein complexes.
BIOPHYSICAL JOURNAL
(2022)
Article
Chemistry, Medicinal
Joseph A. Nicolazzo, Yijun Pan, Ilenia Di Stefano, Kwok H. C. Choy, Sanjeevini Babu Reddiar, Yi Ling Low, Dorothy C. C. Wai, Raymond S. Norton, Liang Jin
Summary: This study evaluated the impact of the Kv1.3 channel blocker HsTX1[R14A] on microglial-mediated neuroinflammation. The results showed that HsTX1[R14A] attenuated the transcription and release of TNF-α and IL-6 in microglia, and reduced the levels of pro-inflammatory mediators in a mouse model of neuroinflammation.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Multidisciplinary Sciences
David A. Eagles, Natalie J. Saez, Bankala Krishnarjuna, Julia J. Bradford, Yanni K. -Y. Chin, Hana Starobova, Alexander Mueller, Melissa E. Reichelt, Eivind A. B. Undheim, Raymond S. Norton, Walter G. Thomas, Irina Vetter, Glenn F. King, Samuel D. Robinson
Summary: This study discovered a peptide toxin, MIITX2-Mg1a, in the venom of the Australian giant red bull ant that mimics vertebrate epidermal growth factor. It acts as a potent agonist of the mammalian EGF receptor ErbB1, causing long-lasting hypersensitivity in mice.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Zhouping Hong, Jyoti Adlakha, Neng Wan, Emily Guinn, Fabian Giska, Kallol Gupta, Thomas J. Melia, Karin M. Reinisch
Summary: Mitoguardin-2 is a mitochondrial protein that binds fatty acids and phospholipids at contacts with the ER or lipid droplets, and can transfer phospholipids between membranes. It plays crucial roles in mitochondrial and lipid droplet biology.
JOURNAL OF CELL BIOLOGY
(2022)
Article
Medicine, Research & Experimental
Sanjeevini Babu Reddiar, Michael de Veer, Brett M. Paterson, Tara Sepehrizadeh, Dorothy C. C. Wai, Agota Csoti, Gyorgy Panyi, Joseph A. Nicolazzo, Raymond S. Norton
Summary: This study investigates the in vivo distribution of HsTX1[R14A] peptide in mice and finds increased uptake in a LPS-induced mouse model of neuroinflammation, as well as accumulation in inflamed joints.
MOLECULAR PHARMACEUTICS
(2023)
Article
Microbiology
Yangqi Gu, Matthew J. Guberman-Pfeffer, Vishok Srikanth, Cong Shen, Fabian Giska, Kallol Gupta, Yuri Londer, Fadel A. Samatey, Victor S. Batista, Nikhil S. Malvankar
Summary: By using cryogenic electron microscopy structure, we revealed the linear and closely stacked haems of OmcZ nanowires, which may account for its electron conductivity. The surface-exposed haems and charge interactions explained the binding interactions between OmcZ nanowires and diverse extracellular electron acceptors, as well as the rearrangement of nanowire network in different biochemical environments. In vitro studies demonstrated how G. sulfurreducens employed a serine protease to control the assembly of OmcZ monomers into nanowires. We found that OmcZ and serine protease are widespread in environmentally important bacteria and archaea, establishing the prevalence of nanowire biogenesis across diverse species and environments.
NATURE MICROBIOLOGY
(2023)
Article
Cell Biology
Taryn J. J. Olivas, Yumei Wu, Shenliang Yu, Lin Luan, Peter Choi, Emily D. D. Guinn, Shanta Nag, Pietro V. V. De Camilli, Kallol Gupta, Thomas J. J. Melia
Summary: ATG9 vesicles serve as the membrane seed for mammalian autophagosomes, as shown by Olivas et al. using nanodisc technology. The integration of ATG9 with expanding autophagosome membranes demonstrates the importance of lipid transfer in autophagosome expansion. This work provides significant insights into the model of autophagosome formation and expands our understanding of the cellular process of autophagy.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Karoline Sanches, Viktor Prypoten, K. George Chandy, David K. Chalmers, Raymond S. Norton
Summary: Peptide toxins like ShK can inhibit the KV1.3 potassium channel and may have potential therapeutic applications for autoimmune and neuroinflammatory diseases. ShK and its homolog HmK exhibit different dynamic behaviors, with ShK showing higher affinity for the KV1.3 channel.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemical Research Methods
Aniruddha Panda, Fabian Giska, Anna L. Duncan, Alexander J. Welch, Caroline Brown, Rachel McAllister, Parameswaran Hariharan, Jean N. D. Goder, Jeff Coleman, Sathish Ramakrishnan, Frederic Pincet, Lan Guan, Shyam Krishnakumar, James E. Rothman, Kallol Gupta
Summary: A mass spectrometry-based approach allows the analysis of integral membrane protein-lipid complexes directly from near-physiological membrane conditions. It provides information about protein oligomeric states, lipid identities, and membrane properties. This method can be used to study how lipid binding regulates neurotransmitter release and how membrane composition regulates the functional oligomeric state of a transporter.
Article
Food Science & Technology
Hayden L. Smith, Peter J. Prentis, Scott E. Bryan, Raymond S. Norton, Daniel A. Broszczak
Summary: The venom delivery system of Phylum Cnidaria is unique, consisting of individual organelles known as nematocysts. Acontia, found in a limited number of sea anemone species, are packed with large nematocysts used for defense. This study identified the venom profile of acontia in Calliactis polypus, revealing limited toxin diversity and a novel toxin with two ShK-like domains. This research provides a foundation for further investigating the function of acontial toxins in sea anemones.
Review
Biochemistry & Molecular Biology
K. George Chandy, Karoline Sanches, Raymond S. Norton
Summary: The voltage-gated potassium channel K(V)1.3 is an important therapeutic target for autoimmune and neuroinflammatory diseases. Recent structural studies have provided insights into the conformational changes of the channel and the mechanism of ion permeation. These findings contribute to a better understanding of the slow inactivation mechanism of K(V) channels and can guide the development of future immunotherapeutics targeting K(V)1.3.
Article
Biochemical Research Methods
Aniruddha Panda, Caroline Brown, Kallol Gupta
Summary: Native mass spectrometry (nMS) is an important analytical tool for studying the organizational states of proteins and their complexes with various ligands. A recent approach utilizes intact and customizable lipid membranes to study membrane proteins, allowing for the determination of lipid specificity and the dissection of chemical and biophysical properties of individual lipids in protein assembly.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2023)
Article
Biochemistry & Molecular Biology
Karoline Sanches, Lauren M. Ashwood, Abisola Ave-Maria Olushola-Siedoks, Dorothy C. C. Wai, Arfatur Rahman, Kashmala Shakeel, Muhammad Umair Naseem, Gyorgy Panyi, Peter J. Prentis, Raymond S. Norton
Summary: Diverse structural scaffolds have been found in peptides from sea anemones, including the common ShKT scaffold. While some ShKT peptides from sea anemones inhibit K-V 1.x channels, others do not. Using NMR and molecular dynamics simulations, a new ShKT peptide from the sea anemone Telmatactis stephensoni was studied and found to have no activity against K-V 1.x channels. The exposure of dyad residues during MD simulations is correlated with the ability of ShKT peptides to block K-V 1.x channels.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2023)
Article
Nanoscience & Nanotechnology
Gerard Walker, Caroline Brown, Xiangyu Ge, Shailesh Kumar, Mandar D. Muzumdar, Kallol Gupta, Moitrayee Bhattacharyya
Summary: The oligomeric organization of membrane proteins in native cell membranes plays a critical role in their function. This study introduces a technique called Native-nanoBleach, which allows for the direct measurement of protein oligomeric distribution in native membranes. By capturing target membrane proteins in native nanodiscs using amphipathic copolymers, high spatial resolution measurements were achieved.
NATURE NANOTECHNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Pol Arranz-Gibert, Koen Vanderschuren, Adrian Haimovich, Anushka Halder, Kallol Gupta, Jesse Rinehart, Farren J. Isaacs
Summary: This study presents a pH-tunable diazotransfer reaction that efficiently converts para-amino-phenyl-alanine (pAF) to para-azido-phenylalanine (pAzF) in proteins. The method selectively modifies pAzF at multiple sites per protein without introducing off-target modifications.
CELL CHEMICAL BIOLOGY
(2022)