Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour
| العنوان: | Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour |
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| المؤلفون: | Lindsay, C, Sitsapesan, M, Chen, W, Venturi, E, Welch, W, Musgaard, M, Sitsapesan, R |
| المصدر: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Binding Sites, Rotamer Toggle, Science, Ryanodine Binding, Molecular Conformation, Ryanodine Receptor Calcium Release Channel, RyR Channels, Triphosphate Group, Predicted Binding Energy, Molecular Dynamics Simulation, musculoskeletal system, Ligands, Article, Molecular Docking Simulation, Structure-Activity Relationship, Adenosine Triphosphate, cardiovascular system, Medicine, Humans, tissues, Ion Channel Gating, Protein Binding |
| الوصف: | ATP is an essential constitutive regulator of cardiac ryanodine receptors (RyR2), enabling small changes in cytosolic Ca2+ to trigger large changes in channel activity. With recent landmark determinations of the full structures of RyR1 (skeletal isoform) and RyR2 using cryo-EM, and identification of the RyR1 ATP binding site, we have taken the opportunity to model the binding of fragments of ATP into RyR2 in order to investigate how the structure of the ATP site dictates the functional responses of ligands attracted there. RyR2 channel gating was assessed under voltage-clamp conditions and by [3H]ryanodine binding studies. We show that even the triphosphate (PPPi) moiety alone was capable of activating RyR2 but produced two distinct effects (activation or irreversible inactivation) that we suggest correspond to two preferred binding locations within the ATP site. Combinations of complementary fragments of ATP (Pi + ADP or PPi + AMP) could not reproduce the effects of ATP, however, the presence of adenosine prevented the inactivating PPPi effects, allowing activation similar to that of ATP. RyR2 appears to accommodate diverse types of molecules, including PPPi, deep within the ATP binding site. The most effective ligands, however, have at least three phosphate groups that are guided into place by a nucleoside. |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::0a88ffa4b509d152b5bda44840a538e6 https://pubmed.ncbi.nlm.nih.gov/30301919 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....0a88ffa4b509d152b5bda44840a538e6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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