v Ab that regulates the flow of sodium into cells Highresolution structures of Na v Ab mutated nonmutated and in complex with a drug compound guanidinium were solved by xray protein crystallography ID: 934383
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Research Details Hypokalemic periodic paralysis (hypoPP) is caused by a mutation in a membrane protein (NavAb) that regulates the flow of sodium into cells.High-resolution structures of NavAb (mutated, non-mutated, and in complex with a drug compound, guanidinium) were solved by x-ray protein crystallography.The disease-state structure showed how sodium leaks through; the guanidinium-bound structure blocked sodium leakage without affecting channel function.
Three states of the membrane protein, NavAb. In the disease state, water-accessible space (magenta) lets sodium ions (gray spheres) pass through. In the rescued state, guanidinium (blue/yellow spheres) prevents sodium leakage.
Scientific AchievementX-ray crystallography of a membrane protein provided a structural understanding of how a single mutation can result in periodic muscle paralysis.Significance and ImpactThe results suggest possible drug designs that could provide relief to patients with a genetic disorder that causes them to be overcome suddenly with profound muscle weakness.
Publication about this research: D. Jiang, T.M. Gamal El-Din, C. Ing, P. Lu, R. Pomès, N. Zheng, and W.A. Catterall, Nature 557, 590 (2018). Work was performed at Lawrence Berkeley National Laboratory, ALS Beamlines 8.2.1 and 8.2.2. Operation of the ALS is supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences program.
Structure Reveals Mechanism of Periodic Paralysis