Molecular Modeling of the Full-length Human TRPV1 Channel in Closed and Desensitized States
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The transient receptor potential vanilloid subtype 1 (TRPV1) is a member of the TRP family gated by vanilloids, heat, and protons. Structurally, TRPV1 subunits have a modular architecture underlying different functionalities, namely stimuli recognition, channel gating, ion selectivity, subunit oligomerization, and regulation by intracellular signaling molecules. Considering modular organization and recent structural information in the ion channel field, we have modeled a full-length TRPV1 by assembly of its major modules: the cytosolic N-terminal, C-terminal, and membrane-spanning region. For N-terminal, we used the ankyrin repeat structure fused with the N-end segment. The membrane domain was modeled with the structure of the eukaryotic, voltage-gated Kv1.2 K+ channel. The C-terminus was cast using the coordinates of HCN channels. The extensive structure–function data available for TRPV1 was used to validate the models in terms of the location of molecular determinants of function in the structure. Additionally, the current information allowed the modeling of the vanilloid receptor in the closed and desensitized states. The closed state shows the N-terminal module highly exposed and accessible to adenosine triphosphate and the C-terminal accessible to phosphoinositides. In contrast, the desensitized state depicts the N-terminal and C-terminal modules close together, compatible with an interaction mediated by Ca2+–calmodulin complex. These models identify potential previously unrecognized intra- and interdomain interactions that may play an important functional role. Although the molecular models should be taken with caution, they provide a helpful tool that yields testable hypothesis that further our understanding on ion channels work in terms of underlying protein structure.
KeywordsVanilloid receptors TRP channel Ion channel Molecular model Homology modeling Structure–function relationship
This work was supported by grants from the Spanish Ministry of Education and Science (MEC) (SAF2006-2580 to A. F. M.), the Fundación Ramón Areces (to A. F. M.), and the Generalitat Valenciana (GV/2007/025 to G. F. B.).
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