Interactions of H562 in the S5 helix with T618 and S621 in the pore helix are important determinants of hERG1 potassium channel structure and function.

ABSTRACT: hERG1 is a member of the cyclic nucleotide binding domain family of K(+) channels. Alignment of cyclic nucleotide binding domain channels revealed an evolutionary conserved sequence HwX(A/G)C in the S5 domain. We reasoned that histidine 562 in hERG1 could play an important structure-function role. To explore this role, we created in silica models of the hERG1 pore domain based on the KvAP crystal structure with Rosetta-membrane modeling and molecular-dynamics simulations. Simulations indicate that the H562 residue in the S5 helix spans the gap between the S5 helix and the pore helix, stabilizing the pore domain, and that mutation at the H562 residue leads to a disruption of the hydrogen bonding to T618 and S621, resulting in distortion of the selectivity filter. Analysis of the simulated p

SUBMITTER: Lees-Miller JP 

PROVIDER: S-EPMC2711401 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature