Structures of SUR2 NBD1 / Drug Complexes Determined with NMR Spectroscopy and Data Driven Docking
Year: 2021
Type: dissertation
Abstract: ATP-sensitive potassium (KATP) channels are formed by four inward-rectifying K+ channels and four regulatory sulfonylurea receptors (SURs). ATP binding and hydrolysis at the SUR nucleotide binding domains (NBDs) regulates opening of the KATP channel pore. The SUR NBDs are also the sites of binding for KATP channel opener (KCO) drugs, which are diverse in structure and can be broadly categorized into several classes of molecules, including benzothiadiazines (diazoxide), cyanoguanidines (pinacidil and P1075), benzopyrans (cromakalim and Y26763), and nicotinamides (nicorandil). Through NMR binding studies, the identification of specific NBD1 residues involved in binding various KCO drugs were identified. The NMR titration data were used to calculate models of NBD1/drug complexes using the data-driven docking program HADDOCK. Knowledge of the bound complex structure will be used for rational design of more effective drugs that will be used to treat diseases associated with impaired KATP channel function, including hyperinsulinism and heart disease.
Source: TSpace (University of Toronto)
Author: Sayewich, Jonathan Scott
Institution: University of Toronto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7132939871