Temperature activated TRP channels or thermoTRPs are among the only proteins that can directly convert temperature changes into changes in channel open probability. In spite of a wealth of functional and structural information, the mechanism of temperature activation remains unknown. We have carefully characterized the repeated activation of TRPV1 by thermal stimuli and discovered a previously unknown inactivation process, which is irreversible. We propose that this form of gating in TRPV1 channels is a consequence of the heat absorption process that leads to channel opening.
Summary data for Figures 1, 2, 3, and 4 have been provided as source data files. The electrophysiological recordings will be made available upon request to the corresponding author.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
© 2018, Sánchez-Moreno et al.
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Nature has inspired the design of improved inhibitors for cancer-causing proteins.
Transition-state (TS) theory has provided the theoretical framework to explain the enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles of conformations, unique TSs would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied the nature of the enzymatic TS for the phosphoryl-transfer step in adenylate kinase by quantum-mechanics/molecular-mechanics calculations. We find a structurally wide set of energetically equivalent configurations that lie along the reaction coordinate and hence a broad transition-state ensemble (TSE). A conformationally delocalized ensemble, including asymmetric TSs, is rooted in the macroscopic nature of the enzyme. The computational results are buttressed by enzyme kinetics experiments that confirm the decrease of the entropy of activation predicted from such wide TSE. TSEs as a key for efficient enzyme catalysis further boosts a unifying concept for protein folding and conformational transitions underlying protein function.