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Conference publicationsAbstractsXIX conferenceHydrophobic anisotropy of scorpion α-toxins surfaceMoscow state university named after M.V.Lomonosov, biology faculty, bioengineering department, 119991, Russia, Moscow, Leninskie Gory,1/12 1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of RAS, Russian Federation, 117997, Moscow, GSP-7, Ul. Miklukho-Maklaya, 16/10 Voltage sensitive Na+-channels (Navs) are integral membrane proteins that selectively control flow of Na+ ions and participate in the generation and propagation of action potentials in excitable cells. Thus, Navs serve as one of the primary targets for various animal neurotoxins, such as scorpion toxins, binding of which alters the membrane potential and the channel activity. Alpha-toxins bind with high affinity to extracellular S3-S4 loop of domain IV of Navs pore-forming α-subunit (site 3), slowing channel inactivation and causing a prolonged action potential. According to their different pharmacological preferences, the scorpion α-toxins can be divided into three subgroups: classical (bind to one or more of nine mamal Navs subtypes), insect α-toxins (active on insect channels) and α-like (toxic to both mammal and insects). Scorpion toxins have already proven to be important pharmacological tools for probing structure and binding surfaces of the Navs and studying the activation and inactivation processes. The search of structural and dynamic features of α-toxins that define selectivity to channels’ subtypes is not only fundamentally significant, but also leads to further development of novel insecticides, based on insect-selective scorpion toxins. α-Toxins (55-65 residues long) are composed of two evolutionary independent and functionally different “domains”: Core-domain, formed by conservative throughout all toxins βαββ-fold, and so called RC-domain, which comprises N-terminal reverse turn (8-12 residues) and C-tail of a protein, that are pulled together by disulphide bond. Using molecular dynamics stimulations and molecular hydrophobicity approach we studied hydrophobic features of scorpion α-toxins surface and their conformational mobility. For the group of classic toxins we discovered that molecules have anisotropic hydrophobic features: RC-domain appears to be significantly more hydrophobic and flexible, comparing to Core-domain. For two insect-active groups there is no such difference between domains. Core-domain, which has similar hydrophobicity for all three toxin groups, is believed to bind to conservative channel surfaces that are invariant in either Nav subtype, whereas RC-domain is thought to interact with variable between subtypes loops. These peculiarities should reflect some features of their channels’ binding surfaces and may serve as a starting point for further discovery of species selectivity mechanism, as well as design of engineered analogs of insect-selective toxins.
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