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Article spatial structure and activity of synthetic fragments of lynx1 and of nicotinic receptor loop c models

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W3115476719.pdf(3.34 MB)
Дата
2021
Авторы
Mineev, K. S.
Kryukova, E. V.
Kasheverov, I. E.
Egorova, N. S.
Tsetlin, V. I.
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Организационные подразделения
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Инженерно-физический институт биомедицины
Цель ИФИБ и стратегия развития – это подготовка высококвалифицированных кадров на базе передовых исследований и разработок новых перспективных методов и материалов в области инженерно-физической биомедицины. Занятие лидерских позиций в биомедицинских технологиях XXI века и внедрение их в образовательный процесс, что отвечает решению практикоориентированной задачи мирового уровня – диагностике и терапии на клеточном уровне социально-значимых заболеваний человека.
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Аннотация
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.Lynx1, membrane-bound protein co-localized with the nicotinic acetylcholine receptors (nAChRs) and regulates their function, is a three-finger protein (TFP) made of three β-structural loops, similarly to snake venom α-neurotoxin TFPs. Since the central loop II of α-neurotoxins is involved in binding to nAChRs, we have recently synthesized the fragments of Lynx1 central loop, including those with the disulfide between Cys residues introduced at N-and C-termini, some of them inhibiting muscle-type nAChR similarly to the whole-size water-soluble Lynx1 (ws-Lynx1). Literature shows that the main fragment interacting with TFPs is the C-loop of both nAChRs and acetylcholine binding proteins (AChBPs) while some ligand-binding capacity is preserved by analogs of this loop, for example, by high-affinity peptide HAP. Here we analyzed the structural organization of these peptide models of ligands and receptors and its role in binding. Thus, fragments of Lynx1 loop II, loop C from the Lymnaea stagnalis AChBP and HAP were synthesized in linear and Cyscyclized forms and structurally (CD and NMR) and functionally (radioligand assay on Torpedo nAChR) characterized. Connecting the C-and N-termini by disulfide in the ws-Lynx1 fragment stabilized its conformation which became similar to the loop II within the1H-NMR structure of ws-Lynx1, the activity being higher than for starting linear fragment but lower than for peptide with free cysteines. Introduced disulfides did not considerably change the structure of HAP and of loop C fragments, the former preserving high affinity for α-bungarotoxin, while, surprisingly, no binding was detected with loop C and its analogs.
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Article spatial structure and activity of synthetic fragments of lynx1 and of nicotinic receptor loop c models / Mineev, K.S. [et al.] // Biomolecules. - 2021. - 11. - № 1. - P. 1-16. - 10.3390/biom11010001
URI
https://www.doi.org/10.3390/biom11010001
 https://www.scopus.com/record/display.uri?eid=2-s2.0-85098784491&origin=resultslist
 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS_CPL&DestLinkType=FullRecord&UT=WOS:000609834000001
 https://openrepository.mephi.ru/handle/123456789/23570
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