FIGURE 4.

Open and closed conformations of PD. (A–C) Open PD model. (A) Matrix of contact variants shows only those PDVs and their contacts, which are unique in the open PD model. Most of coupled variants are associated with either BrS1 or LQT3. (B) Hydrophobic contacts L¹⁷⁶¹:F¹⁴⁶⁵:F¹⁷⁶⁰ and A¹³³⁰:V¹⁴⁶⁸:I¹³³⁴ stabilize, respectively, mutual disposition of helices IIIS6/IVS6 and IIIS5/IIIS6. (C) H-bond S⁹⁴¹:N¹⁴⁶³ stabilizes mutual disposition of helices IIS6/IIIS6. (D–F) Closed PD model. (D) Matrix of contact variants shows only those PDV and their contacts, which are unique in the closed-PD model. (E) Mutual disposition of helices IIIS6 and IVS6 in the closed PD is stabilized by hydrophobic contacts F¹⁴⁶⁵:L¹⁷⁶¹ with side chain conformations different from those in the open-PD model. In coupled LQT3-associated variants, substitutions F¹⁴⁶⁵L or L¹⁷⁶¹F/H would destabilize the closed PD. Mutual disposition of helices IVS5/IVS6 is stabilized by a hydrophobic contact M¹⁷⁶¹:I¹⁶⁶⁰ and a knob-into-hole contact M¹⁷⁶¹:G¹⁶⁶¹. (F) Mutual disposition of helices IS6/IVS6 is stabilized by a tight hydrophobic contact between A⁴¹³ and methylene group of N¹⁷⁷⁴. Replacement of any contact partner with a large residue would destabilize the closed PD, a likely cause of LQT3 associated with these mutations.