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bioRxiv · 10.1101/374041

Cryo-EM Reveals Ligand Induced Allostery Underlying InsP3R Channel Gating

Fan, G.·Baker, M. R.·Wang, Z.·Serysheva, A. B.·Ludtke, S. J.·Baker, M. L.·Serysheva, I. I.
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Abstract

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3R activation is the coupled interplay between binding of InsP3 and Ca2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca2+ through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here we present the electron cryo-microscopy structure of InsP3R1 from rat cerebellum determined to 4.1 [A] resolution in the presence of activating concentrations of Ca2+ and adenophostin A (AdA), a structural mimetic of InsP3 and the most potent known agonist of the channel. Comparison with the 3.9 [A]-resolution structure of InsP3R1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3R channel.

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Fan, G., Baker, M. R., Wang, Z., Serysheva, A. B., Ludtke, S. J., Baker, M. L., Serysheva, I. I.. 2018-07-23. Cryo-EM Reveals Ligand Induced Allostery Underlying InsP3R Channel Gating. https://doi.org/10.1101/374041

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