Табакмахер Валентин Михайлович


Период обученияСтрана, городУчебное заведениеДополнительная информация
2017 Россия, Владивосток Дальневосточный государственный университет, институт химии и прикладной экологии, химический факультет, кафедра биоорганической химии и биотехнологии Диплом химика с отличием
2017 Россия, Владивосток Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения РАН, лаборатория химии пептидов Диплом кандидата химических наук

Научные интересы

Структура и функция белков, молекулярное моделирование, молекулярная биофизика, биоинформатика, молекулярная динамика, структурная биология

Избранные публикации

  1. Kuzmenkov A.I., Peigneur S., Chugunov A.O., Tabakmakher V.M., Efremov R.G., Tytgat J., Grishin E.V., Vassilevski A.A. (2017). C-Terminal residues in small potassium channel blockers OdK1 and OSK3 from scorpion venom fine-tune the selectivity. Biochim. Biophys. Acta 1865 (5), 465–472 [+]

    We report isolation, sequencing, and electrophysiological characterization of OSK3 (α-KTx 8.8 in Kalium and Uniprot databases), a potassium channel blocker from the scorpion Orthochirus scrobiculosus venom. Using the voltage clamp technique, OSK3 was tested on a wide panel of 11 voltage-gated potassium channels expressed in Xenopus oocytes, and was found to potently inhibit Kv1.2 and Kv1.3 with IC50 values of ~331nM and ~503nM, respectively. OdK1 produced by the scorpion Odontobuthus doriae differs by just two C-terminal residues from OSK3, but shows marked preference to Kv1.2. Based on the charybdotoxin-potassium channel complex crystal structure, a model was built to explain the role of the variable residues in OdK1 and OSK3 selectivity.

  2. Kasheverov I.E., Chugunov A.O., Kudryavtsev D.S., Ivanov I.A., Zhmak M.N., Shelukhina I.V., Spirova E.N., Tabakmakher V.M., Zelepuga E.A., Efremov R.G., Tsetlin V.I. (2016). High-Affinity α-Conotoxin PnIA Analogs Designed on the Basis of the Protein Surface Topography Method. Sci Rep 6, 36848 [+]

    Despite some success for small molecules, elucidating structure-function relationships for biologically active peptides - the ligands for various targets in the organism - remains a great challenge and calls for the development of novel approaches. Some of us recently proposed the Protein Surface Topography (PST) approach, which benefits from a simplified representation of biomolecules' surface as projection maps, which enables the exposure of the structure-function dependencies. Here, we use PST to uncover the "activity pattern" in α-conotoxins - neuroactive peptides that effectively target nicotinic acetylcholine receptors (nAChRs). PST was applied in order to design several variants of the α-conotoxin PnIA, which were synthesized and thoroughly studied. Among the best was PnIA[R9, L10], which exhibits nanomolar affinity for the α7 nAChR, selectivity and a slow wash-out from this target. Importantly, these mutations could hardly be delineated by "standard" structure-based drug design. The proposed combination of PST with a set of experiments proved very efficient for the rational construction of new bioactive molecules.

  3. Gladkikh I., Monastyrnaya M., Zelepuga E., Sintsova O., Tabakmakher V., Gnedenko O., Ivanov A., Hua K.F., Kozlovskaya E. (2015). New Kunitz-Type HCRG Polypeptides from the Sea Anemone Heteractis crispa. Mar Drugs 13 (10), 6038–63 [+]

    Sea anemones are a rich source of Kunitz-type polypeptides that possess not only protease inhibitor activity, but also Kv channels toxicity, analgesic, antihistamine, and anti-inflammatory activities. Two Kunitz-type inhibitors belonging to a new Heteractis crispa RG (HCRG) polypeptide subfamily have been isolated from the sea anemone Heteractis crispa. The amino acid sequences of HCRG1 and HCRG2 identified using the Edman degradation method share up to 95% of their identity with the representatives of the HCGS polypeptide multigene subfamily derived from H. crispa cDNA. Polypeptides are characterized by positively charged Arg at the N-terminus as well as P1 Lys residue at their canonical binding loop, identical to those of bovine pancreatic trypsin inhibitor (BPTI). These polypeptides are shown by our current evidence to be more potent inhibitors of trypsin than the known representatives of the HCGS subfamily with P1Thr. The kinetic and thermodynamic characteristics of the intermolecular interactions between inhibitors and serine proteases were determined by the surface plasmon resonance (SPR) method. Residues functionally important for polypeptide binding to trypsin were revealed using molecular modeling methods. Furthermore, HCRG1 and HCRG2 possess anti-inflammatory activity, reducing tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) secretions, as well as proIL-1β expression in lipopolysaccharide (LPS)-activated macrophages. However, there was no effect on nitric oxide (NO) generation.

  4. Kasheverov I.E., Kudryavtsev D.S., Ivanov I.A., Zhmak M.N., Chugunov A.O., Tabakmakher V.M., Zelepuga E.A., Efremov R.G., Tsetlin V.I. (2015). Rational design of new ligands for nicotinic receptors on the basis of α-conotoxin PnIA. Dokl. Biochem. Biophys. 461, 106–9 [+]

    A variety of different subtypes of nicotinic acetylcholine receptors (nAChRs) and their involvement in a number of diseases and pathologies (Parkinson’s and Alzheimer’s diseases, schizophrenia, myasthenia, nicotine addiction) dictates the needs in potent and selective ligands for each subtype. These ligands can be used as a tool for detection and characterization of the distinct nAChR subtypes, as well as be the basis for drug design. Novel cholinergic ligands can emerge in the result of search among natural sources or design (with the use of modern computer modeling) on the basis of known molecules. The significance of the first way was confirmed in our hands by the detection of affinities of a set of marine alkaloids from sponges and ascidians towards some receptor subtypes. The most active of them — makaluvamines — showed micromolar affinity for muscle and neuronal α7 nAChRs. Application of the recently presented Protein Surface Topography method to known natural antagonist of some neuronal nAChRs — α-conotoxin PnIA — resulted in design of new potent analogs with nanomolar affinities for α7 nAChR. Radioactive derivatives of these analogs were successfully applied in radioligand tests for characterization of novel compounds and could be perspective as well for detection of α7 nAChR in the various preparations. Combining these two ways (search and design) was demonstrated in the synthesis of small peptide compounds on the basis of discovered by us in venom of Burmese Viper linear peptide azemiopsin — powerful blocker of muscle-type nAChRs. Some designed peptides have retained a certain affinity to receptor and showed high practical potential: in the absence of toxicity they contributed to the reduction of facial wrinkles (patent application for cosmetic use RU2013102410; PCT/RU2014/000032).

  5. Tabakmakher V.M., Sintsova O.V., Krivoshapko O.N., Zelepuga E.A., Monastyrnaya M.M., Kozlovskaya E.P. (2015). Analgesic effect of novel Kunitz-type polypeptides of the sea anemone Heteractis crispa. Dokl. Biochem. Biophys. 461, 80–3 ID:1593
  6. Tabakmakher V.M., Monastyrnaya M.M., Leichenko E.V., Gladkikh I.N., Zelepuga E.A., Chausova V.E., Tkacheva E.S., Agafonova I.G., Kozlovskaya E.P. (2013). Biologically active polypeptides of sea anemones: Structure, function, and prospects for application. Russian Journal of Marine Biology 39 (5), 311–320 ID:1786
  7. Zelepuga E.A., Tabakmakher V.M., Chausova V.E., Monastyrnaia M.M., Isaeva M.P., Kozlovskaia E.P. (2012). [Interaction of sea amemone Heteractis crispa Kunitz type polypeptides with pain vanilloid receptor TRPV1: in silico investigation]. Bioorg. Khim. 38 (2), 185–98 [+]

    Using methods of molecular biology we defined the structures of the 31 sea anemone Heteractis crispa genes encoding polypeptides which are structurally homologous to the Kunitz proteinase inhibitor family. Identified amino acid sequences have point residue substitutions, high degree of homology with sequences of known H. crispa Kunitz family members, and represent a combinatorial library of polypeptides. We generated their three-dimensional structures by homologous modeling methods. Analysis of their molecular electrostatic potential enabled us to divide given polypeptides into three clusters. One of them includes polypeptides APHC1, APHC2 and APHC3, which were earlier shown to possess a unique property of inhibiting of the pain vanilloid receptor TRPV1 in vitro and providing the analgesic effects in vivo in addition to their trypsin inhibitory activity. Molecular docking made possible establishing the spatial structure of the complexes, the nature of the polypeptides binding with TRPV1, as well as functionally important structural elements involved in the complex formation. Structural models have enabled us to propose a hypothesis contributing to understanding the APHC1-3 impact mechanism for the pain signals transduction by TRPV1: apparently, there is an increase of the receptor relaxation time resulted in binding of its two chains with the polypeptide molecule, which disrupt the functioning of the TRPV1 and leads to partial inhibition of signal transduction in electrophysiological experiments.

  8. Isaeva M.P., Chausova V.E., Zelepuga E.A., Guzev K.V., Tabakmakher V.M., Monastyrnaya M.M., Kozlovskaya E.P. (2012). A new multigene superfamily of Kunitz-type protease inhibitors from sea anemone Heteractis crispa. Peptides 34 (1), 88–97 [+]

    Despite a considerable number of publications devoted to isolation and physicochemical properties of protease inhibitors from sea anemones, virtually nothing is known about the structure of the genes, and the nature of their isoforms diversity. Using the PCR-based cloning approach we discovered the Kunitz-type multigene superfamily composed of distinct gene families (GS-, RG-, GG-, and GN-gene families). It has been identified only three full-length GS-transcripts indicating a much greater variety of Kunitz homologs in Heteractis crispa. We have examined an exon-intron structure of GS-genes; an open reading frame is interrupted by a single intron located at the middle of the signal peptide. 33 deduced mature GS-polypeptides have been categorized into three groups according to the nature of a P1 residue. Some of them corresponded to native Kunitz-type protease inhibitors earlier isolated from H. crispa. The deduced GS-polypeptide sequences demonstrated diverse charge distribution ranging from the local point charges forms to the overall positive ones. We have suggested that the GS-gene family has evolved through gene tandem duplication followed by adaptive divergence of the P1 residue in the reactive site selected for divergent functions in paralogs. The expansion of this Kunitz-type multigene superfamily during evolution is lineage-specific, providing the tropical sea anemone H. crispa with the ability to interact an increasing diversity of the preys and predators. Our results show that the Kunitz-type polypeptides are encoded by a multigene superfamily and realized via a combinatory Kunitz-type library in the H. crispa tentacles venom.