Арсеньев Александр Сергеевич

Избранные публикации

  1. Shenkarev Z.O., Finkina E.I., Nurmukhamedova E.K., Balandin S.V., Mineev K.S., Nadezhdin K.D., Yakimenko Z.A., Tagaev A.A., Temirov Y.V., Arseniev A.S., Ovchinnikova T.V. (2010). Isolation, structure elucidation, and synergistic antibacterial activity of a novel two-component lantibiotic lichenicidin from Bacillus licheniformis VK21. Biochemistry 49 (30), 6462–72 [+]

    A novel synergetic lantibiotic pair, Lchalpha(3249.51 Da) and Lchbeta(3019.36 Da), termed lichenicidin VK21, was isolated from the producer strain Bacillus licheniformis VK21. Chemical and spatial structures of Lchalphaand Lchbeta were determined. Each peptide contains 31 amino acid residues linked by 4 intramolecular thioether bridges and the N-terminal 2-oxobutyryl group. Spatial structures of Lchalpha and Lchbetawere studied by NMR spectroscopy in methanol solution. Lchalpha peptide displays structural homology with mersacidin-like lantibiotics and involves relatively well-structured N- and C-terminal domains connected by a flexible loop stabilized by thioether bridge Ala11-S-Ala21. In contrast, the Lchbetapeptide represents prolonged hydrophobic alpha-helix flanked with more flexible N- and C-terminal domains. A lantibiotic cluster of the Bacillus licheniformis VK21 genome which comprises the structural genes, lchA1 and lchA2, encoding the lantibiotics precursors, as well as the gene of a modifying enzyme lchM1, was amplified and sequenced. The mature peptides, Lchalphaand Lchbetainteract synergistically to possess antibiotic activity against Gram-positive bacteria within a nanomolar concentration range, though the individual peptides were shown to be active at micromolar concentrations. Our results afford molecular insight into mechanism of lichenicidin VK21 action.

  2. Mineev K.S., Bocharov E.V., Pustovalova Y.E., Bocharova O.V., Chupin V.V., Arseniev A.S. (2010). Spatial Structure of the Transmembrane Domain Heterodimer of ErbB1 and ErbB2 Receptor Tyrosine Kinases. J. Mol. Biol. 400 (2), 231–243 [+]

    Growth factor receptor tyrosine kinases of the ErbB family play a significant role in vital cellular processes and various cancers. During signal transduction across plasma membrane, ErbB receptors are involved in lateral homodimerization and heterodimerization with proper assembly of their extracellular single-span transmembrane (TM) and cytoplasmic domains. The ErbB1/ErbB2 heterodimer appears to be the strongest and most potent inducer of cellular transformation and mitogenic signaling compared to other ErbB homodimers and heterodimers. Spatial structure of the heterodimeric complex formed by TM domains of ErbB1 and ErbB2 receptors embedded into lipid bicelles was obtained by solution NMR. The ErbB1 and ErbB2 TM domains associate in a right-handed alpha-helical bundle through their N-terminal double GG4-like motif T(648)G(649)X(2)G(652)A(653) and glycine zipper motif T(652)X(3)S(656)X(3)G(660), respectively. The described heterodimer conformation is believed to support the juxtamembrane and kinase domain configuration corresponding to the receptor active state. The capability for multiple polar interactions, along with hydrogen bonding between TM segments, correlates with the observed highest affinity of the ErbB1/ErbB2 heterodimer, implying an important contribution of the TM helix-helix interaction to signal transduction.

  3. Bocharov E.V., Mayzel M.L., Volynsky P.E., Mineev K.S., Tkach E.N., Ermolyuk Y.S., Schulga A.A., Efremov R.G., Arseniev A.S. (2010). Left-handed dimer of EphA2 transmembrane domain: Helix packing diversity among receptor tyrosine kinases. Biophys. J. 98 (5), 881–9 [+]

    The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands control a diverse array of cell-cell interactions in the developing and adult organisms. During signal transduction across plasma membrane, Eph receptors, like other receptor tyrosine kinases, are involved in lateral dimerization and subsequent oligomerization presumably with proper assembly of their single-span transmembrane domains. Spatial structure of dimeric transmembrane domain of EphA2 receptor embedded into lipid bicelle was obtained by solution NMR, showing a left-handed parallel packing of the transmembrane helices (535-559)(2). The helices interact through the extended heptad repeat motif L(535)X(3)G(539)X(2)A(542)X(3)V(546)X(2)L(549) assisted by intermolecular stacking interactions of aromatic rings of (FF(557))(2), whereas the characteristic tandem GG4-like motif A(536)X(3)G(540)X(3)G(544) is not used, enabling another mode of helix-helix association. Importantly, a similar motif AX(3)GX(3)G as was found is responsible for right-handed dimerization of transmembrane domain of the EphA1 receptor. These findings serve as an instructive example of the diversity of transmembrane domain formation within the same family of protein kinases and seem to favor the assumption that the so-called rotation-coupled activation mechanism may take place during the Eph receptor signaling. A possible role of membrane lipid rafts in relation to Eph transmembrane domain oligomerization and Eph signal transduction was also discussed.

  4. Goncharuk S.A., Shulga A.A., Ermolyuk Y.S., Kuzmichev P.K., Sobol V.A., Bocharov E.V., Chupin V.V., Arseniev A.S., Kirpichnikov M.P. (2009). Bacterial synthesis, purification, and solubilization of membrane protein KCNE3, a regulator of voltage-gated potassium channels. Biochemistry Mosc. 74 (12), 1344–9 [+]

    Описан эффективный способ получения мембранного белка KCNE3, а также его изотопно-меченых производных (15N-, 13C-), в количествах, достаточных для проведения структурно-функциональных исследований. Очищенный белковый препарат в составе мицелл различных детергентов охарактеризован методами динамического светорассеяния, КД-спектроскопии и ЯМР-спектроскопии. Показано, что в мицеллах DPC/LDAO белок находится в мономерной форме и принимает преимущественно альфа-спиральную конформацию. Наличие кросс-пиков от всех глицинов в 15N-HSQC–спектре ЯМР, а также относительно небольшая ширина линий (~20 Гц) подтверждают высокое качество полученного образца и возможность получения структурно-динамической информации о KCNE3 методом гетероядерной спектроскопии ЯМР высокого разрешения.

  5. Krabben L., vanRossum B.J., Jehle S., Bocharov E., Lyukmanova E.N., Schulga A.A., Arseniev A., Hucho F., Oschkinat H. (2009). Loop 3 of short neurotoxin II is an additional interaction site with membrane-bound nicotinic acetylcholine receptor as detected by solid-state NMR spectroscopy. J. Mol. Biol. 390 (4), 662–71 [+]

    The contact area of neurotoxin II from Naja naja oxiana when interacting with the membrane-bound nicotinic acetylcholine receptor from Torpedo californica was determined by solid-state, magic-angle spinning NMR spectroscopy. For this purpose, the carbon signals for more than 90% of the residues of the bound neurotoxin were assigned. Differences between the solution and solid-state chemical shifts of the free and bound form of the toxin are confined to distinct surface regions. Loop II of the short toxin was identified as the main interaction site. In addition, loop III of neurotoxin II shows several strong responses defining an additional interaction site. A comparison with the structures of alpha-cobratoxin bound to the acetylcholine-binding protein from snail species Lymnaea stagnalis and Aplysia californica, and of alpha-bungarotoxin bound to an extracellular domain of an alpha-subunit of the receptor reveals different contact areas for long and short alpha-neurotoxins.

  6. Polyansky A.A., Volynsky P.E., Arseniev A.S., Efremov R.G. (2009). Adaptation of a membrane-active peptide to heterogeneous environment. I. Structural plasticity of the peptide. The journal of physical chemistry. B 113 (4), 1107–19 [+]

    В статье приводится детальное описание различных факторов, определяющих процесс взаимодействия мембрано-активного пептида (неспецифический переносчик—пенетратин) с липидными бислоями разного состава. К ключевым факторам следует отнести: конформационную подвижность пептида, способность аминокислотных остатков образовывать специфические контакты с другими остатками пептида, а также полярными головками липидов.

  7. Polyansky A.A., Volynsky P.E., Arseniev A.S., Efremov R.G. (2009). Adaptation of a membrane-active peptide to heterogeneous environment. II. The role of mosaic nature of the membrane surface. The journal of physical chemistry. B 113 (4), 1120–6 [+]

    В статье постулируется мозаичная гидрофобно-гдрофильная организация поверхности липидной мембраны. Рассматривается влияние гетерогенности полярных свойств границы раздела вода-липиды на процесс связывания мембрано-активных агентов (на примере неспецифического пептидного переносчика — пенетратина).

  8. Dubovskii P.V., Volynsky P.E., Polyansky A.A., Karpunin D.V., Chupin V.V., Efremov R.G., Arseniev A.S. (2008). Three-dimensional structure/hydrophobicity of latarcins specifies their mode of membrane activity. Biochemistry 47 (11), 3525–33 [+]

    Latarcins, linear peptides from the Lachesana tarabaevi spider venom, exhibit a broad-spectrum antimicrobial activity, likely acting on the bacterial cytoplasmic membrane. We study their spatial structures and interaction with model membranes by a combination of experimental and theoretical methods to reveal the structure-activity relationship. In this work, a 26 amino acid peptide, Ltc1, was investigated. Its spatial structure in detergent micelles was determined by (1)H nuclear magnetic resonance (NMR) and refined by Monte Carlo simulations in an implicit water-octanol slab. The Ltc1 molecule was found to form a straight uninterrupted amphiphilic helix comprising 8-23 residues. A dye-leakage fluorescent assay and (31)P NMR spectroscopy established that the peptide does not induce the release of fluorescent marker nor deteriorate the bilayer structure of the membranes. The voltage-clamp technique showed that Ltc1 induces the current fluctuations through planar membranes when the sign of the applied potential coincides with the one across the bacterial inner membrane. This implies that Ltc1 acts on the membranes via a specific mechanism, which is different from the carpet mode demonstrated by another latarcin, Ltc2a, featuring a helix-hinge-helix structure with a hydrophobicity gradient along the peptide chain. In contrast, the hydrophobic surface of the Ltc1 helix is narrow-shaped and extends with no gradient along the axis. We have also disclosed a number of peptides, structurally homologous to Ltc1 and exhibiting similar membrane activity. This indicates that the hydrophobic pattern of the Ltc1 helix and related antimicrobial peptides specifies their activity mechanism. The latter assumes the formation of variable-sized lesions, which depend upon the potential across the membrane.

  9. Bocharov E.V., Mineev K.S., Volynsky P.E., Ermolyuk Y.S., Tkach E.N., Sobol A.G., Chupin V.V., Kirpichnikov M.P., Efremov R.G., Arseniev A.S. (2008). Spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J. Biol. Chem. 283 (11), 6950–6 [+]

    Proper lateral dimerization of the transmembrane domains of receptor tyrosine kinases is required for biochemical signal transduction across the plasma membrane. The spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 embedded into lipid bicelles was obtained by solution NMR, followed by molecular dynamics relaxation in an explicit lipid bilayer. ErbB2 transmembrane segments associate in a right-handed alpha-helical bundle through the N-terminal tandem GG4-like motif Thr652-X3-Ser656-X3-Gly660, providing an explanation for the pathogenic power of some oncogenic mutations.

  10. Vereshaga Y.A., Volynsky P.E., Pustovalova J.E., Nolde D.E., Arseniev A.S., Efremov R.G. (2007). Specificity of helix packing in transmembrane dimer of the cell death factor BNIP3: a molecular modeling study. Proteins 69 (2), 309–25 [+]

    Предложен вычислительный метод предсказания пространственной структуры димеров трансмембранных альфа-спиралей. Подход основан на применении модели неявно заданной мембраны и конформационного поиска методом Монте-Карло в пространстве двугранных углов пептидов. Эффективность метода продемонстрирована на примере трансмембранного домена проапоптотического митохондриального белка BNIP3.

  11. Chugunov A.O., Novoseletsky V.N., Nolde D.E., Arseniev A.S., Efremov R.G. (2007). Method to assess packing quality of transmembrane alpha-helices in proteins. 1. Parametrization using structural data. Journal of chemical information and modeling 47 (3), 1150–62 [+]

    Integral membrane proteins (MPs) are pharmaceutical targets of exceptional importance. Modern methods of three-dimensional protein structure determination often fail to supply the fast growing field of structure-based drug design with the requested MPs' structures. That is why computational modeling techniques gain a special importance for these objects. Among the principal difficulties limiting application of these methods is the low quality of the MPs' models built in silico. In this series of two papers we present a computational approach to the assessment of the packing "quality" of transmembrane (TM) alpha-helical domains in proteins. The method is based on the concept of protein environment classes, whereby each amino acid residue is described in terms of its environment polarity and accessibility to the membrane. In the first paper we analyze a nonredundant set of 26 TM alpha-helical domains and compute the residues' propensities to five predefined classes of membrane-protein environments. Here we evaluate the proposed approach only by various test sets, cross-validation protocols and ability of the method to delimit the crystal structure of visual rhodopsin, and a number of its erroneous theoretical models. More advanced validation of the method is given in the second article of this series. We assume that the developed "membrane score" method will be helpful in optimizing computer models of TM domains of MPs, especially G-protein coupled receptors.

  12. Chugunov A.O., Novoseletsky V.N., Nolde D.E., Arseniev A.S., Efremov R.G. (2007). Method to assess packing quality of transmembrane alpha-helices in proteins. 2. Validation by "correct vs misleading" test. Journal of chemical information and modeling 47 (3), 1163–70 [+]

    We describe a set of tests designed to check the ability of the new "membrane score" method (see the first paper of this series) to assess the packing quality of transmembrane (TM) alpha-helical domains in proteins. The following issues were addressed: (1) Whether there is a relation between the score (S(mem)) of a model and its closeness to the "nativelike" conformation? (2) Is it possible to recognize a correct model among misfolded and erroneous ones? (3) To what extent the score of a homology-built model is sensitive to errors in sequence alignment? To answer the first question, two test cases were considered: (i) Several models of bovine aquaporin-1 (target protein) were built on the structural templates provided by its homologs with known X-ray structure. (ii) Side chains in the spatial models of visual rhodopsin and cytochrome c oxidase were rebuilt based on the backbone scaffolds taken from their crystal structures, and the resulting models were iteratively fitted into the full-atom X-ray conformations. It was shown that the higher the S(mem) value of a model is, the lower its root-mean-square deviation is from the "correct" (crystal) structure of a target. Furthermore, the "membrane score" method successfully identifies the rhodopsin crystal structure in an ensemble of "rotamer-type" decoys, thus providing the way to optimize mutual orientations of alpha-helices in models of TM domains. Finally, being applied to a set of homology models of rhodopsin built on its crystal structure with systematically shifted alignment, the approach demonstrates a prominent ability to detect alignment errors. We therefore assume that the "membrane score" method will be helpful in optimization of in silico models of TM domains in proteins, especially those in GPCRs.

  13. Chugunov A.O., Novoseletsky V.N., Arseniev A.S., Efremov R.G. (2007). A novel method for packing quality assessment of transmembrane alpha-helical domains in proteins. Biochemistry Mosc. 72 (3), 293–300 [+]

    Here we present a novel method for assessment of packing quality for transmembrane (TM) domains of alpha-helical membrane proteins (MPs), based on analysis of available high-resolution experimental structures of MPs. The presented concept of protein-membrane environment classes permits quantitative description of packing characteristics in terms of membrane accessibility and polarity of the nearest protein groups. We demonstrate that the method allows identification of native-like conformations among the large set of theoretical MP models. The developed "membrane scoring function" will be of use for optimization of TM domain packing in theoretical models of MPs, first of all G-protein coupled receptors.

  14. Pyrkov T.V., Kosinsky Y.A., Arseniev A.S., Priestle J.P., Jacoby E., Efremov R.G. (2007). Complementarity of hydrophobic properties in ATP-protein binding: a new criterion to rank docking solutions. Proteins 66 (2), 388–98 [+]

    Анализ экспериментально установленных пространственных структур комплексов АТФ-белок был проведен с целью выявить основные закономерности, определяющие молекулярное узнавание аденин-белок. Было показано что основную роль играют гидрофобные котакты и стэкинг, и разработан эффективный метод учета этих взаимодействий в аденин-специфичной оценочной функции.

  15. Efremov R.G., Chugunov A.O., Pyrkov T.V., Priestle J.P., Arseniev A.S., Jacoby E. (2007). Molecular lipophilicity in protein modeling and drug design. Curr. Med. Chem. 14 (4), 393–415 [+]

    Hydrophobic interactions play a key role in the folding and maintenance of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g. drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic (lipophilic) properties of these molecules is indispensable for the development of efficient computational methods in drug design. One possible solution to the problem lies in application of a concept of the 3-dimensional molecular hydrophobicity potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical parameters evaluated from octanol-water partition coefficients (log P) of numerous chemical compounds. It permits detailed assessment of the hydrophobic and/or hydrophilic properties of various parts of molecules and may be useful in analysis of protein-protein and protein-ligand interactions. This review surveys recent applications of MHP-based techniques to a number of biologically relevant tasks. Among them are: (i) Detailed assessment of hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the modeling of structure, dynamics, and function of globular and membrane proteins, membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in docking simulations for ligands binding to receptors. It is demonstrated that the application of the MHP-based techniques in combination with other molecular modeling tools (e.g. Monte Carlo and molecular dynamics simulations, docking, etc.) permits significant improvement to the standard computational approaches, provides additional important insights into the intimate molecular mechanisms driving protein assembling in water and in biological membranes, and helps in the computer-aided drug discovery process.

  16. Volynsky P.E., Bocharov E.V., Nolde D.E., Vereshaga Y.A., Mayzel M.L., Mineev K.S., Mineeva E.V., Pustovalova Yu.E., Gagnidze I.A., Efremov R.G., Arseniev A.S. (2006). Solution of the Spatial Structure of Dimeric Transmembrane Domains of Proteins by Heteronuclear NMR Spectroscopy and Molecular Modeling. Biophysics 51 (S1), S23–S27 [+]

    Membrane proteins play an important role in various biological processes. An approach combining
    NMR spectroscopy with molecular modeling was used to study the spatial structure and intramolecular dynamics of protein transmembrane domains consisting of two interacting α-helices. The approach was tested with model transmembrane domains and yielded detailed atomic-level data on the protein–protein and protein–lipid interactions.

  17. Kasheverov I.E., Chiara D.C., Zhmak M.N., Maslennikov I.V., Pashkov V.S., Arseniev A.S., Utkin Y.N., Cohen J.B., Tsetlin V.I. (2006). alpha-Conotoxin GI benzoylphenylalanine derivatives. (1)H-NMR structures and photoaffinity labeling of the Torpedo californica nicotinic acetylcholine receptor. FEBS J. 273 (7), 1373–88 [+]

     

    С использованием фотоактивируемого производного одного из конотоксинов методом фотоаффинной модификации проведено частичное картирование лиганд-связывающего участка природного холинорецептора. Исходя из полученных данных, компьютерным моделированием предположена возможность двух ориентаций молекулы пептида в этом участке.

     

  18. Feofanov A.V., Sharonov G.V., Astapova M.V., Rodionov D.I., Utkin Y.N., Arseniev A.S. (2005). Cancer cell injury by cytotoxins from cobra venom is mediated through lysosomal damage. Biochem. J. 390 (Pt 1), 11–8 [+]

    Статья посвящена исследованию механизмов цитотоксического действия цитотоксинов (ЦТ) из яда кобр. В данной работе показано, что ЦТ 1 и 2 из яда кобры Naja oxiana, ЦТ 1 из Naja haje и ЦТ 3 из Naja kaouthia способны накапливаться в лизосомах клеток промиелоцитарной лейкемии человека HL60 и аденокарциномы легкого человека A549. Кинетика и концентрационная зависимость накопления ЦТ в лизосомах согласуется с кинетикой и концентрационной зависимостью гибели клеток, что свидетельствует о том, что лизосомы могут быть одной из мишеней ЦТ, а воздействие на эту мишень заключается в концентрационно-зависимой пермеабилизации мембраны лизосом.

  19. Sharonov G.V., Feofanov A.V., Bocharova O.V., Astapova M.V., Dedukhova V.I., Chernyak B.V., Dolgikh D.A., Arseniev A.S., Skulachev V.P., Kirpichnikov M.P. (2005). Comparative analysis of proapoptotic activity of cytochrome c mutants in living cells. Apoptosis 10 (4), 797–808 [+]

    В работе докладывается о разработке метода измерения проапоптотическй активности экзогенного цитохрома с в живых клетках. Метод основан на введении белка в цитоплазму клетки с помощью электропорации и выявлении с помощью флуоресцентной микроскопии признаков развития апоптоза в клетках. С помощью данного метода были измерены относительные про-апоптозные активности лошадиного цитохрома с и четырех мутантных вариантов данного белка. Обнаружено, что аминокислотная замена К72W полностью блокирует про-апоптозную активность цитохрома с, но не влияет на его «дыхательную» функцию. Методом КОМИРСИ была впервые оценена минимальная цитоплазматическая концентрация лошадиного цитохрома с, необходимая для индукции апоптоза в клетках WEHI-3b.

  20. Korolkova Y.V., Bocharov E.V., Angelo K., Maslennikov I.V., Grinenko O.V., Lipkin A.V., Nosyreva E.D., Pluzhnikov K.A., Olesen S.P., Arseniev A.S., Grishin E.V. (2002). New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1. J. Biol. Chem. 277 (45), 43104–9 [+]

    The scorpion toxin BeKm-1 is unique among a variety of known short scorpion toxins affecting potassium channels in its selective action on ether-a-go-go-related gene (ERG)-type channels. BeKm-1 shares the common molecular scaffold with other short scorpion toxins. The toxin spatial structure resolved by NMR consists of a short alpha-helix and a triple-stranded antiparallel beta-sheet. By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ERG K+ (HERG) channel. The most critical residues (Tyr-11, Lys-18, Arg-20, Lys-23) are located in the alpha-helix and following loop whereas the "traditional" functional site of other short scorpion toxins is formed by residues from the beta-sheet. Thus the unique location of the binding site of BeKm-1 provides its specificity toward the HERG channel.

  21. Efremov R.G., Nolde D.E., Vergoten G., Arseniev A.S. (1999). A solvent model for simulations of peptides in bilayers. I. Membrane-promoting alpha-helix formation. Biophys. J. 76 (5), 2448–59 [+]

    В работе дается описание неявно заданной модели мембраны. Показана эффективность модели в предсказании доли альфа-спиральной конформации для нескольких гомопептидов (поли-Leu, поли-Val, поли-Ile, поли-Gly) методом Монте-Карло.

  22. Arseniev A.S., Bystrov V.F., Lomize A.L., Ovchinnikov Yu.A. (1985). 1H-NMR study of gramicidin A transmembrane ion channel. Head-to-head right-handed, single-stranded helices. FEBS Lett. 186 (2), 168–174 [+]

    The structure of [Val1] gramicidin A incorporated into sodium dodecyl-d25 sulphate micelles has been studied by two-dimensional proton NMR spectroscopy. Analysis of nuclear Overhauser effects, spin-spin couplings and solvent accessibility of NH groups show that the conformation of the Na+ complex of gramicidin A in detergent micelles, which in many ways mimic the phospholipid bilayer of biomembranes, is an N-terminal to N-terminal (head-to-head) dimer Image formed by two right-handed, single-stranded β6.3 helices with 6.3 residues per turn, differing from Urry's structure by handedness of the helices.