Eag-related channels (EAG, hERG, ELK) all share a highly conserved region bearing homology with cyclic- nucleotide binding domains of a variety of other proteins including cyclic nucleotide-gated channels. However, most evidence indicates this domain has evolved to serve a different, but unknown, function in Eag-related channels. This application introduces a new X-ray crystal structure for the EAG1 cyclic nucleotide homology domain (CNBhD) and proposes experiments directed by structural considerations to probe its function as an allosteric modulator of channel gating. Molecules interacting with this domain and modifying channel behavior will be identified through a layered screening approach. A range of biochemical and functional approaches reflecting complementary strengths of the participating laboratories will be employed. This project is expected to address a long-standing question in the field regarding the structure and function of CNBhD's, and produce reagents that will ultimately help define the functional role of EAG1 channels in the brain and facilitate chemotherapeutic drug development.
EAG1 channels are a major component of the electrical machinery of the brain and are also highly expressed in cancerous cells outside the brain, making them a potential target for chemotherapy. This proposal seeks to understand the inner workings of channel behavior, which are currently poorly understood. This new knowledge, combined with the proposed identification of new chemicals that can interfere or enhance channel function, may ultimately help define EAG1 function in the brain and facilitate the development of therapeutic drugs.
|Pointer, Kelli B; Clark, Paul A; Eliceiri, Kevin W et al. (2016) Non-torsadogenic human Ether-Ã -go-go Related Gene (hERG) inhibitors are associated with better survival for high hERG-expressing glioblastoma patients. Clin Cancer Res :|
|Marques-Carvalho, Maria JoÃ£o; Oppermann, Johannes; MuÃ±oz, Eva et al. (2016) Molecular Insights into the Mechanism of Calmodulin Inhibition of the EAG1 Potassium Channel. Structure 24:1742-1754|
|Liu, Fang; Jones, David K; de Lange, Willem J et al. (2016) Cotranslational association of mRNA encoding subunits of heteromeric ion channels. Proc Natl Acad Sci U S A 113:4859-64|
|Jones, David K; Liu, Fang; Dombrowski, Natasha et al. (2016) Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death. Prog Biophys Mol Biol 120:67-76|
|Harley, Carol A; Starek, Greg; Jones, David K et al. (2016) Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain. Proc Natl Acad Sci U S A 113:9916-21|
|Morais-Cabral, JoÃ£o H; Robertson, Gail A (2015) The enigmatic cytoplasmic regions of KCNH channels. J Mol Biol 427:67-76|
|Jones, David K; Liu, Fang; Vaidyanathan, Ravi et al. (2014) hERG 1b is critical for human cardiac repolarization. Proc Natl Acad Sci U S A 111:18073-7|
|Adaixo, Ricardo; Harley, Carol A; Castro-Rodrigues, Artur F et al. (2013) Structural properties of PAS domains from the KCNH potassium channels. PLoS One 8:e59265|