Abstract
The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by “unzipping” the extracellular domain and the transmembrane domain, mediated by a unique segment within the β3-β4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors.
Highlights
The PAC1R ECD structure has been determined experimentally[11, 12], the 7TM structure as well as the relative position and orientation of the ECD remains unknown
Our analyses suggest that the transition is initiated by the separation of the β3-β4 loop from extracellular loop 3 (ECL3)
When we removed the 21-aa sequence from our final models and tested the consequence of lost ECD-ECL3 contacts with MD simulations, the open-state model showed a rapid transition toward a G3-like closed state within 0.1 μs — in line with that observed for GCGR14, which lacks a comparable segment in the β3-β4 loop
Summary
The PAC1R ECD structure has been determined experimentally[11, 12], the 7TM structure as well as the relative position and orientation of the ECD remains unknown. According to the shortest transition pathways, there are relatively short conversion paths among the closed states (G1, G2, and G3) but the open state (G4) is rather remote (see Fig. 1A and Supplementary Table 2), suggesting some partition in the conformational states. For conversions within closed states, the rate-limiting step mainly involves a helix-coil transition at the linker (see Fig. 1A).
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