6mu2

Publication Abstract from PubMed

Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca(2+) 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 Ca(2+) that switches the ion conduction pathway between closed and open states to enable the passage of Ca(2+) 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 Ca(2+) 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.

Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating.,Fan G, Baker MR, Wang Z, Seryshev AB, Ludtke SJ, Baker ML, Serysheva II Cell Res. 2018 Nov 23. pii: 10.1038/s41422-018-0108-5. doi:, 10.1038/s41422-018-0108-5. PMID:30470765^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.