7ddk | pdb_00007ddk
Crystal structures of Na+,K+-ATPase in complex with rostafuroxin
Structural highlights
FunctionAT1A1_PIG This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients. Publication Abstract from PubMedThe sodium pump (Na(+), K(+)-ATPase, NKA) is vital for animal cells, as it actively maintains Na(+) and K(+) electrochemical gradients across the cell membrane. It is a target of cardiotonic steroids (CTSs) such as ouabain and digoxin. As CTSs are almost unique strong inhibitors specific to NKA, a wide range of derivatives has been developed for potential therapeutic use. Several crystal structures have been published for NKA-CTS complexes, but they fail to explain the largely different inhibitory properties of the various CTSs. For instance, although CTSs are thought to inhibit ATPase activity by binding to NKA in the E2P state, we do not know if large conformational changes accompany binding, as no crystal structure is available for the E2P state free of CTS. Here, we describe crystal structures of the BeF(3)(-) complex of NKA representing the E2P ground state and then eight crystal structures of seven CTSs, including rostafuroxin and istaroxime, two new members under clinical trials, in complex with NKA in the E2P state. The conformations of NKA are virtually identical in all complexes with and without CTSs, showing that CTSs bind to a preformed cavity in NKA. By comparing the inhibitory potency of the CTSs measured under four different conditions, we elucidate how different structural features of the CTSs result in different inhibitory properties. The crystal structures also explain K(+)-antagonism and suggest a route to isoform specific CTSs. Binding of cardiotonic steroids to Na(+),K(+)-ATPase in the E2P state.,Kanai R, Cornelius F, Ogawa H, Motoyama K, Vilsen B, Toyoshima C Proc Natl Acad Sci U S A. 2021 Jan 7;118(1):e2020438118. doi: , 10.1073/pnas.2020438118. PMID:33318128[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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