Cryo‐electron microscopy of Na+,K+‐ATPase reveals how the extracellular gate locks in the E2·2K+ state

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Abstract
Na+,K+‐ATPase (NKA) is one of the most important members of the P‐type ion‐translocating ATPases and plays a pivotal role in establishing electrochemical gradients for Na+ and K+ across the cell membrane. Presented here is a 3.3 Å resolution structure of NKA in the E2·2K+ state solved by cryo‐electron microscopy. It is a stable state with two occluded K+ after transferring three Na+ into the extracellular medium and releasing inorganic phosphate bound to the cytoplasmic P domain. We describe how the extracellular ion pathway wide open in the E2P state becomes closed and locked in E2·2K+, linked to events at the phosphorylation site more than 50 Å away. We also show, although at low resolution, how ATP binding to NKA in E2·2K+ relaxes the gating machinery and thereby accelerates the transition into the next step, that is, the release of K+ into the cytoplasm, more than 100 times.
Funding Information
  • Japan Society for the Promotion of Science (JP19H00975, JP21K06109)
  • Lundbeck Foundation (R223‐2016‐595)
  • Novo Nordisk Fonden (NNF13OC0006555, NNF14OC0013409)
  • Takeda Science Foundation

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