Structural Basis Of An Inherited Herg1 Long Qt Mutant

Mutations in human ether-a-go-go related K+ channel gene hERG1 are a common cause of Long QT syndrome (LQTS), an electrical disorder of the heart that predisposes individuals to sudden death. Of these, changes to the pore domain are associated with a greater risk of life-threatening arrhythmias. One such mutation N629D, located adjacent to the selectivity filter, causes loss of function and altered ion selectivity. We have shown that the selectivity filter sequence of non-selective cation channel NaK shows striking similarity to that of hERG1, and that mutagenic transformation of the NaK filter into hERG1's generates a structurally canonical K+ filter. Here, using this hERG1-like NaK as a structural model, we reveal the molecular mechanisms that underlie channel dysfunction in the N629D mutant. The NaK/hERG N629D filter crystal structure obtained at 2.8 Å show that N629D induces a dramatic conformational rearrangements in the extracellular vestibule that extend to the filter, disrupting K+ binding sites to cause loss of ion selectivity. These changes involve a 180 deg rotation of the Phenylalanine 66 at the selectivity filter (equivalent to position Phe627 in hERG1) and an intrinsic sensitivity to the nature of the permeant ion. These findings provide insight into the hERG1 selectivity filter and offer a new biophysical tool for the study of the molecular mechanisms underlying LQTS pore mutants at atomic level.