Many transient receptor potential (TRP) channels respond to diverse stimuli and conditionally conduct small and large cations. Such functional plasticity is presumably enabled by a uniquely dynamic ion selectivity filter that is regulated by physiological agents. What is currently missing is a "photo series" of intermediate structural states that directly address this hypothesis and reveal specific mechanisms behind such dynamic channel regulation. Here, we exploit cryoelectron microscopy (cryo-EM) to visualize conformational transitions of the capsaicin receptor, TRPV1, as a model to understand how dynamic transitions of the selectivity filter in response to algogenic agents, including protons, vanilloid agonists, and peptide toxins, permit permeation by small and large organic cations. These structures also reveal mechanisms governing ligand binding substates, as well as allosteric coupling between key sites that are proximal to the selectivity filter and cytoplasmic gate. These insights suggest a general framework for understanding how TRP channels function as polymodal signal integrators.
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution
Capsaicin activation of the pain receptor, VR1: multiple open states from both partial and full binding
Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy
Contribution of the putative inner-pore region to the gating of the transient receptor potential vanilloid subtype 1 channel (TRPV1)
A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain
Engineering extended membrane scaffold proteins for self-assembly of soluble nanoscale lipid bilayers
H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations
Role of the outer pore domain in transient receptor potential vanilloid 1 dynamic permeability to large cations.
Coupled binding mechanism of three sodium ions and aspartate in the glutamate transporter homologue GltTk
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