排序方式: 共有8条查询结果,搜索用时 15 毫秒
1
1.
Valentin M. Tabakmakher Andrei M. Gigolaev Steve Peigneur Nikolay A. Krylov Jan Tytgat Anton O. Chugunov Alexander A. Vassilevski Roman G. Efremov 《Biophysical journal》2021,120(12):2471-2481
The α-Hairpinins are a family of plant defense peptides with a common fold presenting two short α-helices stabilized by two invariant S–S-bridges. We have shown previously that substitution of just two amino acid residues in a wheat α-hairpinin Tk-AMP-X2 leads to Tk-hefu-2 that features specific affinity to voltage-gated potassium channels KV1.3. Here, we utilize a combined molecular modeling approach based on molecular dynamics simulations and protein surface topography technique to improve the affinity of Tk-hefu-2 to KV1.3 while preserving its specificity. An important advance of this work compared with our previous studies is transition from the analysis of various physicochemical properties of an isolated toxin molecule to its consideration in complex with its target, a membrane-bound ion channel. As a result, a panel of computationally designed Tk-hefu-2 derivatives was synthesized and tested against KV1.3. The most active mutant Tk-hefu-10 showed a half-maximal inhibitory concentration of ~150 nM being >10 times more active than Tk-hefu-2 and >200 times more active than the original Tk-hefu. We conclude that α-hairpinins provide an attractive disulfide-stabilized scaffold for the rational design of ion channel inhibitors. Furthermore, the success rate can be considerably increased by the proposed “target-based” iterative strategy of molecular design. 相似文献
2.
Tabakmakher V. M. Kuzmenkov A. I. Gigolaev A. M. Pinheiro-Junior E. L. Peigneur S. Efremov R. G. Tytgat J. Vassilevski A. A. 《Journal of Evolutionary Biochemistry and Physiology》2021,57(2):386-403
Journal of Evolutionary Biochemistry and Physiology - In mammals, about 40 isoforms of voltage-gated potassium channels (KVs) have been found. To study such a variety of KVs, substances are needed... 相似文献
3.
Biologically active polypeptides of sea anemones: Structure, function, and prospects for application
V. M. Tabakmakher M. M. Monastyrnaya E. V. Leichenko I. N. Gladkikh E. A. Zelepuga V. E. Chausova E. S. Tkacheva I. G. Agafonova E. P. Kozlovskaya 《Russian Journal of Marine Biology》2013,39(5):311-320
This paper presents the results of a structure-functional study of neurotoxins, actinoporins, and proteinase inhibitors from the tropical sea anemone Heteractis crispa (= Radianthus macrodactylus) and the low boreal sea anemone Oulactis orientalis. The new data significantly contribute to the knowledge of the mechanisms of action of polypeptides from marine coelenterates and can be useful for solving practical problems of the biotechnological development of medicines. 相似文献
4.
Zelepuga EA Tabakmakher VM Chausova VE monastyrnaia MM Isaeva MP Kozlovskaia ÉP 《Bioorganicheskaia khimiia》2012,38(2):185-198
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. 相似文献
5.
6.
E. A. Zelepuga V. M. Tabakmakher V. E. Chausova M. M. Monastyrnaya M. P. Isaeva E. P. Kozlovskaya 《Russian Journal of Bioorganic Chemistry》2012,38(2):159-170
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 protease inhibitor family. The identified sequences
have single-point amino acid substitutions, a high degree of homology with sequences of known Kunitz family members from H. crispa, and represent a combinatorial library of polypeptides. We generated their three-dimensional structures by methods of homology
modeling. Analysis of their molecular electrostatic potential allowed the division of the polypeptides into three clusters.
One of them includes polypeptides APHC1, APHC2, and APHC3 which have been shown to possess, in addition to their trypsin inhibitory
activity, a unique property of inhibiting the pain vanilloid receptor TRPV1 in vitro and providing the analgesic effects in
vivo. The spatial structure of the polypeptide complexes with TRPV1, the nature of the interactions, as well as functionally
important structural elements involved in the complex formation, were established by molecular docking technique. The designed
models allowed us to propose a hypothesis contributing to the understanding of how APHC1-APHC3 affect the pain signals transduction
by TRPV1: apparently, relaxation time of the receptor increases due to binding of its two chains with a polypeptide molecule
which disrupts functioning of TRPV1 and leads to partial inhibition of the signal transduction in electrophysiological experiments. 相似文献
7.
Valentin M. Tabakmakher Andrei M. Gigolaev Steve Peigneur Nikolay A. Krylov Jan Tytgat Anton O. Chugunov Alexander A. Vassilevski Roman G. Efremov 《Biophysical journal》2021,120(12):2471
The α-Hairpinins are a family of plant defense peptides with a common fold presenting two short α-helices stabilized by two invariant S–S-bridges. We have shown previously that substitution of just two amino acid residues in a wheat α-hairpinin Tk-AMP-X2 leads to Tk-hefu-2 that features specific affinity to voltage-gated potassium channels KV1.3. Here, we utilize a combined molecular modeling approach based on molecular dynamics simulations and protein surface topography technique to improve the affinity of Tk-hefu-2 to KV1.3 while preserving its specificity. An important advance of this work compared with our previous studies is transition from the analysis of various physicochemical properties of an isolated toxin molecule to its consideration in complex with its target, a membrane-bound ion channel. As a result, a panel of computationally designed Tk-hefu-2 derivatives was synthesized and tested against KV1.3. The most active mutant Tk-hefu-10 showed a half-maximal inhibitory concentration of ∼150 nM being >10 times more active than Tk-hefu-2 and >200 times more active than the original Tk-hefu. We conclude that α-hairpinins provide an attractive disulfide-stabilized scaffold for the rational design of ion channel inhibitors. Furthermore, the success rate can be considerably increased by the proposed “target-based” iterative strategy of molecular design. 相似文献
8.
Anti‐migratory activity of marine alkaloid monanchocidin A – proteomics‐based discovery and confirmation 下载免费PDF全文
1