Abstract
AbstractCholesterol oligomers reside in multiple membrane protein X‐ray crystal structures. Yet, there is no direct link between these oligomers and a biological function. Here we present the structural and functional details of a cholesterol dimer that stabilizes the inactivated state of an inward‐rectifier potassium channel KirBac1.1. K+ efflux assays confirm that high cholesterol concentration reduces K+ conductance. We then determine the structure of the cholesterol‐KirBac1.1 complex using Xplor‐NIH simulated annealing calculations driven by solid‐state NMR distance measurements. These calculations identified an α–α cholesterol dimer docked to a cleft formed by adjacent subunits of the homotetrameric protein. We compare these results to coarse grain molecular dynamics simulations. This is one of the first examples of a cholesterol oligomer performing a distinct biological function and structural characterization of a conserved promiscuous lipid binding region.
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