Panel A shows the structural organization of the H C N 1 channel, highlighting the C-linker region, including the elbow and shoulder domains, with selected residues subjected to directional perturbations grouped into distinct clusters based on their structural influence. Panel B shows the predicted displacement pattern of the C-linker derived from linear response analysis, where vectors indicate the direction of movement following applied perturbations. Panel C shows a comparison of displacement patterns illustrating a coordinated rotational-like rearrangement of the C-linker region, with arrows representing relative direction and proportional magnitude of movement across the structure.
Comparison of predicted and experimentally measured displacements of the C-linker in cAMP-free and cAMP-bound HCN1 channel. (A) Perturbation forces in different directions applied to Ala-425 at the tip of the so-called elbow in the C-linker. Perturbation directions were sorted in four different clusters (red, blue, yellow, and green) depending on their conformational impact on the “shoulder domain.” (B) Predicted displacements of C-linker from LRT analysis following perturbation at Ala-425 force in direction of yellow arrows in A. (C) The predicted displacement vectors in B mimic the experimentally observed iris-like leftward movement in the apo-to-holo-transition of HCN1 cryo-EM structures. The arrows indicate the direction of the respective displacement, while their overall magnitude (length) is uninformative (arbitrary units); however, the ratio of their lengths is a quantifier. Visualizations are top views from an extracellular perspective. Data, with permission, are reproduced by Groß et al. (2018).