Year: 2014
Type: article
Abstract: X-ray crystallography has provided tremendous insight into the different structural states of membrane proteins and, in particular, of ion channels. However, the molecular forces that determine the thermodynamic stability of a particular state are poorly understood. Here we analyze the different X-ray structures of an inwardly rectifying potassium channel (Kir1.1) in relation to functional data we obtained for over 190 mutants in Kir1.1. This mutagenic perturbation analysis uncovered an extensive, state-dependent network of physically interacting residues that stabilizes the pre-open and open states of the channel, but fragments upon channel closure. We demonstrate that this gating network is an important structural determinant of the thermodynamic stability of these different gating states and determines the impact of individual mutations on channel function. These results have important implications for our understanding of not only K+ channel gating but also the more general nature of conformational transitions that occur in other allosteric proteins.
Source: Structure
Institutions: Christian-Albrechts-Universität zu Kiel, University of Oxford
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $1,702
Awards: G1502084111, G1778333383, CCP-BioSim: Biomolecular simulation at the life sciences interface, Functional validation of a structural gating model for the Kir potassium channel, G504678512, OMSys: Towards a systems model of a bacterial outer membrane, G7080100828, G712558274, Crowding and Complexity: Simulation Studies of Biologically Realistic Membrane Models, G8080688728, MemProtMD: A resource for membrane proteins, G8858561294
OpenAlex ID: W2113759125