Article
Biochemistry & Molecular Biology
Ravikumar Reddi, Kimberly Matulef, Erika Riederer, Pierre Moenne-Loccoz, Francis Valiyaveetil
Summary: Regulation of ion conduction through the pore of a K+ channel involves coordinated action of the activation gate and inactivation gate, with the W67F mutant of the KcsA channel showing reduced inactivation and enhanced activation rate. Structural studies provide insights into the allosteric pathway and highlight the importance of ion occupancy at the S2 site for channel inactivation.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
David K. Jones
Summary: Cardiac hERG channels consist of hERG 1a and hERG 1b subunits, which drive cardiac action potential repolarization by regulating the movement of voltage sensor domains (VSDs). This study found that VSD relaxation delays pore closure during repolarization and that the hERG 1a PAS domain plays a role in regulating VSD movement. These findings provide the first recordings of hERG gating charge at physiological temperature and demonstrate the presence of VSD relaxation in hERG channels at physiological temperature.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Hongbo Chen, Jiahua Deng, Qiang Cui, Baron Chanda, Katherine Henzler-Wildman
Summary: By combining experimental results with molecular dynamics simulations, this study reveals that the engineered temperature-sensitive variant of the Shaker potassium channel has the same overall secondary structure as the wild-type channel, but exhibits local changes in backbone torsion angles near the substitution sites (V369S and F370S). Notably, these structural differences lead to increased hydration of specific regions in the temperature-sensitive variant at higher temperatures, highlighting the impact of subtle differences in primary structure on solvation and temperature-dependent activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Takushi Shimomura, Kiichi Hirazawa, Yoshihiro Kubo
Summary: This study reveals that different conformations of DII-S4 determine the gating modes in Two-pore channels (TPCs), with the intermediate state representing the PIP2-gating mode. TPC3 is primarily voltage-dependent, while TPC2 is PIP2-gated and nonvoltage-dependent. Furthermore, the antidepressant desipramine induces voltage dependence in TPC2, and the flavonoid naringenin biases the mode preference from PIP2-gating to desipramine-induced voltage gating.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yoshiaki Kise, Go Kasuya, Hiroyuki H. Okamoto, Daichi Yamanouchi, Kan Kobayashi, Tsukasa Kusakizako, Tomohiro Nishizawa, Koichi Nakajo, Osamu Nureki
Summary: Mechanisms of modulation of Kv4 channel complexes by auxiliary subunits are central to the physiological function of channels in the brain and heart. The structures of Kv4.2-KChIP1 and Kv4.2-DPP6S complexes reveal that KChIP1 prevents N-type inactivation and stabilizes the S6 conformation, while DPP6S interacts with the S1 and S2 helices to accelerate voltage-dependent movement. KChIP1 and DPP6S do not directly interact with each other in the ternary complex, suggesting two distinct modes of modulation contribute to evoke A-type currents.
Article
Multidisciplinary Sciences
Tamer M. Gamal El-Din, Timothy Lantin, Christopher W. Tschumi, Barbara Juarez, Meagan Quinlan, Julia H. Hayano, Jin Li, Larry S. Zweifel, William A. Catterall
Summary: Autism spectrum disorder affects over 1% of children in the United States, resulting in social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis through genome sequencing has identified over 500 genes with mutations in ASD, suggesting that altered control of action potential generation by gating pore current through mutant K(v)7 channels may be a potential pathogenic mechanism in autism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Pharmacology & Pharmacy
Zheng Zequn, Lian Jiangfang
Summary: The rapidly activating delayed rectifier K+ current generated by the cardiac hERG potassium channel is crucial for cardiac repolarization. The unique inward rectification characteristics of the hERG channel depend on gating regulation, involving key structural domains and single amino acid residues. Identifying critical molecules involved in the regulation of gating kinetics for the hERG channel requires high-resolution structures and molecular dynamics simulation models.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Rong Shen, Yilin Meng, Benoit Roux, Eduardo Perozo
Summary: This study investigates the conformational changes in voltage-sensing domains (VSDs) during the voltage activation process. Through molecular dynamics simulations and experimental validations, the researchers identified four different conformations visited in the VSD of the phosphatase Ci-VSP. The results provide insights into the energetics and mechanism of voltage activation in VSDs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Rym ElFessi, Oussema Khamessi, Najet Srairi-Abid, Jean-Marc Sabatier, Jan Tytgat, Steve Peigneur, Riadh Kharrat
Summary: Bot33 is a new short polypeptide purified from the venom of Buthus occitanus tunetanus scorpion. It has potential therapeutic effects and displays a different mode of action on ion channels compared to other scorpion toxins, which is worth further exploration.
Review
Physiology
Luigi Catacuzzeno, Franco Conti, Fabio Franciolini
Summary: This article reviews the retrospective on gating currents from their first recording in 1973 to the present day and their contribution to understanding channel gating. The past 50 years have witnessed great progress in elucidating the mechanisms of channel gating through the recording and analysis of gating currents. The review covers the development of the concept of gating particles and gating currents, early studies on specific channels, expansion to other channels and non-channel structures, and the translation of gating-charge/voltage-sensor movements into pore opening and associated pathologies.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Article
Multidisciplinary Sciences
Willy Carrasquel-Ursulaez, Ignacio Segura, Ignacio Diaz-Franulic, Felipe Echeverria, Yenisleidy Lorenzo-Ceballos, Nicolas Espinoza, Maximiliano Rojas, Jose Antonio Garate, Eduardo Perozo, Osvaldo Alvarez, Fernando D. Gonzalez-Nilo, Ramon Latorre
Summary: This study demonstrates that two arginines in the transmembrane segment S4 function as the gating charges of BK channels, and the energy landscape of gating particles is tuned by a network of salt bridges in the voltage sensor domain (VSD). Unlike Kv channels, the charge movement in BK seems limited to a small displacement of the guanidinium moieties of R210 and R213.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Marco Colombini, Kevin Barnes, Kai-Ti Chang, Muhsin H. Younis, Vicente M. Aguilella
Summary: Gram-negative bacteria have a variety of channel-forming proteins in their outer membrane, some of which show voltage dependence. Triplin, a trimeric channel former, has steep voltage dependence and high inter-subunit cooperativity. Detailed molecular insights into these unusual properties have been obtained at the single-molecule level.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Materials Science, Multidisciplinary
Nidhin Thomas, Kranthi K. Mandadapu, Ashutosh Agrawal
Summary: Experimental studies have shown that different lipids can affect the voltage control of Kv channels, with POPA restricting the movement of the voltage sensor domain, cholesterol increasing membrane rigidity, and DOTAP reducing the effect of electrostatic forces by regulating the dielectric constant. The electromechanical model predictions are in agreement with experimental observations, providing insights into the lipid-dependent gating of Kv channels.
MATHEMATICS AND MECHANICS OF SOLIDS
(2022)
Article
Multidisciplinary Sciences
Venkata Shiva Mandala, Roderick MacKinnon
Summary: Voltage-dependent ion channels regulate the opening of their pores by sensing the membrane voltage. Cryo-electron microscopy was used to visualize the movement of S4 helix in the mammalian Eag voltage-dependent potassium channel, explaining how the voltage sensor locks the pore shut at hyperpolarizing membrane voltages.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Shuo Han, Sophia Peng, Joshua Vance, Kimberly Tran, Nhu Do, Nauy Bui, Zhenhua Gui, Shizhen Wang
Summary: This article investigates the conformational dynamics and gating mechanisms of voltage-gated proton (Hv) channels. By using single-molecule fluorescence resonance energy transfer (smFRET) with purified human voltage-gated proton (hHv1) channels reconstituted in liposomes, the real-time conformational trajectories of the S4 segment were observed. The results demonstrate that voltage and pH gradient can shift the conformational dynamics of the S4 segment, controlling the gating of the channel. The authors propose a kinetic model to explain the voltage and pH gating mechanisms in Hv channels, which may have implications for understanding the voltage sensing and gating in other voltage-gated ion channels.
Article
Dermatology
Mikhail A. Shulepko, Maxim L. Bychkov, Zakhar O. Shenkarev, Dmitrii S. Kulbatskii, Alexey M. Makhonin, Alexander S. Paramonov, Anton O. Chugunov, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova
Summary: Mal de Meleda is a palmoplantar keratoderma associated with mutations in the SLURP-1 gene, which controls the growth, differentiation, and apoptosis of keratinocytes. Mutations in different regions of SLURP-1 have varying effects on its antiproliferative activity against keratinocytes. This study provides insights into the functional and structural implications of SLURP-1 mutations in the pathogenesis of Mal de Meleda.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2021)
Article
Biochemistry & Molecular Biology
M. Yu. Myshkin, A. S. Paramonov, D. S. Kulbatskii, E. A. Surkova, A. A. Berkut, A. A. Vassilevski, E. N. Lyukmanova, M. P. Kirpichnikov, Z. O. Shenkarev
Summary: Voltage-gated sodium channels have modular architecture with five membrane domains, where peripheral voltage-sensing domains are responsible for channel activation and rapid inactivation. Gating modifier toxins from arthropod venoms interact with these domains, potentially serving as prototypes for new drugs. In this study, the toxin Hm-3 showed high affinity to VSD-III of human skeletal muscle Na(V)1.4 channel, with specific residues likely interacting with the channel and the lipid bilayer.
Article
Biochemistry & Molecular Biology
Maxim A. Dubinnyi, Peter Dubovskii, Vladislav G. Starkov, Yuri N. Utkin
Summary: In this study, a pair of cytotoxins from Naja kaouthia crude venom were selected for sequence-structure relationship clarification. Through chromatography, mass spectroscopy, and NMR spectroscopy, the toxins were separated, identified, and their spatial structures determined. It was found that the loop-2 region of cytotoxins adopts an omega-loop shape, with a tightly-bound water molecule in its cavity, showing spatial similarity with other proteins in this family.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Chemistry, Organic
Sergey L. Deev, Tatyana S. Shestakova, Zakhar O. Shenkarev, Alexander S. Paramonov, Igor A. Khalymbadzha, Oleg S. Eltsov, Valery N. Charushin, Oleg N. Chupakhin
Summary: The study synthesized selectively N-15-labeled tetrazolo[1,5-b][1,2,4]-triazines and tetrazolo[1,5-a]pyrimidines, and investigated their structures and equilibrium states in solution using NMR spectroscopy. The incorporation of N-15-label(s) affected the structure and coupling constants of the compounds, providing an effective method to study tetrazole isomers and azide form.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Alexander S. Paramonov, Mikhail A. Shulepko, Alexey M. Makhonin, Maxim L. Bychkov, Dmitrii S. Kulbatskii, Andrey M. Chernikov, Mikhail Yu Myshkin, Sergey Shabelnikov, Zakhar O. Shenkarev, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova
Summary: In this study, we identified and analyzed the genomes of starfish A. rubens and A. planci, and predicted several proteins containing three-finger domains. One of these proteins, Lystar5, was expressed in A. rubens and negatively modulated the cholinergic system in hippocampal neurons.
Article
Biochemistry & Molecular Biology
Maxim M. M. Zaigraev, Ekaterina N. N. Lyukmanova, Alexander S. S. Paramonov, Zakhar O. O. Shenkarev, Anton O. O. Chugunov
Summary: Ly6/uPAR proteins with GPI-anchors have various positions and orientations on the membrane surface, regardless of the linker length between the LU domain and GPI-anchor. The proteins interact with the membrane through polypeptide parts and glycans. Different proteins have different contact regions with the membrane and unique orientations, indicating that GPI-anchoring does not determine the optimal pre-orientation for receptor interaction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Irina S. Panina, Sergey V. Balandin, Andrey V. Tsarev, Anton O. Chugunov, Andrey A. Tagaev, Ekaterina I. Finkina, Daria V. Antoshina, Elvira V. Sheremeteva, Alexander S. Paramonov, Jasmin Rickmeyer, Gabriele Bierbaum, Roman G. Efremov, Zakhar O. Shenkarev, Tatiana V. Ovchinnikova
Summary: To date, several lantibiotics have been found to target lipid II, a peptidoglycan precursor in bacterial cytoplasmic membrane. The alpha-component of lichenicidin, a two-component lantibiotic, contains potential lipid II binding sites. NMR spectroscopy and MD simulations provided evidence that the C-terminal domain of lichenicidin interacts with lipid II. The contact area of lipid II includes pyrophosphate, disaccharide residues, and bactoprenol's first isoprene units.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Organic
Valentin N. N. Petushkov, Matvey V. V. Vavilov, Igor A. A. Ivanov, Rustam H. H. Ziganshin, Natalia S. S. Rodionova, Ilia V. V. Yampolsky, Aleksandra S. S. Tsarkova, Maxim A. A. Dubinnyi
Summary: The bioluminescence of Siberian earthworms Henlea sp. can be enhanced by low molecular weight activators ActH and ActS found in the hot extracts. ActH was identified as a riboflavin analog and ActS is a novel compound. Both ActH and ActS can activate the bioluminescence of Henlea sp., providing insights for further characterization of the bioluminescence system.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Biology
Zakhar O. Shenkarev, Yuri M. Chesnokov, Maxim M. Zaigraev, Anton O. Chugunov, Dmitrii S. Kulbatskii, Milita V. Kocharovskaya, Alexander S. Paramonov, Maxim L. Bychkov, Mikhail A. Shulepko, Dmitry E. Nolde, Roman A. Kamyshinsky, Evgeniy O. Yablokov, Alexey S. Ivanov, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova
Summary: The alpha 7-nAChR is a potential therapeutic target for cognitive dysfunction and cancer treatment. WTX, a non-conventional neurotoxin, shows weak affinity to the alpha 7-nAChR. Our study reveals significant differences in the interaction mode between non-conventional neurotoxins and nicotinic receptors compared to classical neurotoxins, emphasizing the importance of the membrane for their interaction.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Alexey A. Kotlobay, Maxim A. Dubinnyi, Sergey I. Kovalchuk, Aleksandr P. Makhin, Vasily S. Miturich, Maria S. Lyakhovich, Danielle M. Fontaine, Tara L. Southworth, Vladimir I. Shmygarev, Oleg N. Yatskin, Bruce R. Branchini, Ilia Yampolsky, Zinaida M. Kaskova
Summary: This study investigates the bioluminescence phenomenon in insects, specifically focusing on the chemistry of light emission in Diptera species. The authors identify the oxyluciferin structure in Keroplatus spp. as 3-hydroxykynurenic acid. Additionally, they provide evidence of the relationship between the bioluminescent systems of Orfelia and Keroplatus, while noting that the mechanisms of light emission are not identical.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Renata I. Zagitova, Konstantin V. Purtov, Aleksandr S. Shcheglov, Konstantin S. Mineev, Maxim A. Dubinnyi, Ivan N. Myasnyanko, Olga A. Belozerova, Vera G. Pakhomova, Valentin N. Petushkov, Natalia S. Rodionova, Vladislav A. Lushpa, Elena B. Guglya, Sergey Kovalchuk, Valeri B. Kozhemyako, Jeremy D. Mirza, Anderson G. Oliveira, Ilia V. Yampolsky, Zinaida M. Kaskova, Aleksandra S. Tsarkova
Summary: In this study, three compounds were isolated and structurally elucidated from the Chaetomorpha linum algae. These compounds showed bioluminescence activity with Chaetopterus luciferase in the presence of Fe2+ ions. They are derivatives of polyunsaturated fatty acid peroxides. The study also confirmed the broad substrate specificity of the luciferase by obtaining and demonstrating the activity of their structural analogues in the bioluminescence reaction.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Organic
Yaroslav V. Bolt, Maxim A. Dubinnyi, Veronika V. Litvinenko, Alexey A. Kotlobay, Olga A. Belozerova, Renata I. Zagitova, Vladimir I. Shmygarev, Oleg N. Yatskin, Elena B. Guglya, Vadim S. Kublitski, Mikhail S. Baranov, Ilia V. Yampolsky, Zinaida M. Kaskova, Aleksandra S. Tsarkova
Summary: We have achieved the first total synthesis of racemic Odontosyllisundecimdonta luciferin. This compound consists of a 6-6-5-fused tricyclic skeleton with three sulfur atoms in different electronic states. The key transformation involves the tandem condensation of a bifunctional thiol-phosphonate, obtained from dimethyl acetylene dicarboxylate, with benzothiophene-6,7-quinone. This convergent approach allows for the synthesis of the target compound with a previously unreported fused heterocyclic core in 11 steps, facilitating the unambiguous confirmation of the chemical structure of Odontosyllis luciferin by 2D-NMR spectroscopy.
Meeting Abstract
Cell Biology
Maxim Bychkov, Olga Shlepova, Zakhar Shenkarev, Ekaterina Lyukmanova, Mikhail Shulepko
CELL DEATH DISCOVERY
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
A. Tyurin, V. Alferova, T. Kravchenko, G. Kudryakova, A. Paramonov, A. Baranova, S. Efimova, O. Ostroumova, I. Osterman, A. Mardanov, N. Ravin, Z. Shenkarev, V. Korshun
Meeting Abstract
Biochemistry & Molecular Biology
E. Fedorenko, M. Shulepko, M. Bychkov, A. Paramonov, M. Kirpichnikov, Z. Shenkarev, E. Lyukmanova