Robert A. Pearlstein

TL;DR: A homology model of the homo-tetrameric pore domain of HERG is created using the crystal structure of the bacterial potassium channel, KvAP, as a template and key aromatic groups of the blockers are predicted to form multiple simultaneous ring stacking and hydrophobic interactions among the eight aromatic residues lining the pore.

TL;DR: A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA and a homology model of HERG was constructed from the crystal structure of the open MthK potassium channel.

TL;DR: Calculation of the kinetic rate constants determining each step in the permeation event allows derivation of structure-kinetic relationships of permeation, and this work finds that the desolvation/loss of hydrogen bonding required to leave the membrane partitioned position controls the membrane flip-flop rate, whereas membrane partitioning determines the rate of leaving the membrane.

TL;DR: It is proposed that the fast kon and entropically driven thermodynamics observed for PCSK9‐EGF‐A binding stem from the functional replacement of water occupying stable PCSK 9 hydration sites, and that the relatively fast koff observed for EGF‐A unbinding stems from the limited displacement of solvent occupying unstable hydration Sites.