Probing the Potassium Channel Inhibitor Binding Site

探测钾通道抑制剂结合位点

• 批准号: 6936219
• 负责人: Sarah J. YOHANNAN
• 金额: $ 4.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936219
• 关键词: Escherichia coli; X ray crystallography; binding sites; crystallization; electrophysiology; ion channel blocker; long QT syndrome; membrane model; membrane proteins; model design /development; pharmacokinetics; postdoctoral investigator; potassium channel; protein binding; protein structure function; site directed mutagenesis; transfection /expression vector; voltage gated channel; yeasts

DESCRIPTION (provided by applicant): Potassium channels contain a conserved ion conduction pore that contains a promiscuous ligand binding site able to bind a multitude of drugs. Determining the precise location of the site, and the mechanism by which binding occurs has been elusive. Small sequence differences in the channels affect hydrophobicity, aromaticity, cavity size, and channel gating which are all thought to affect ligand binding affinity. KcsA, the bacterial channel of known structure, is a suitable model for studying the pore region of the family of potassium channels due to the relative ease with which it can be mutated, highly expressed, and crystallized, I propose to establish a system using the KcsA potassium channel to study the features of the channel cavity using mutagenesis along with both structural biology and electrophysiology methods. I will also express and crystallize HERG (human ether-a-go-go-related gene), a potassium channel present in heart muscle cells. HERG is of particular interest because many common drugs block its channel causing loss of function, which results in an abnormal electrical signal (long-QT syndrome) that can lead to the arrythmia Torsades de Pointes and sometimes sudden heart failure.

描述（由申请人提供）：