7D92

Crystal Structure of the Na+,K+-ATPase in the E2P state with bound Mg2+ and anthroylouabain (P4(3)2(1)2 symmetry)

Summary for 7D92

• Entry DOI: 10.2210/pdb7d92/pdb
• Related: 6KPU 6KPV 6KPW 6KPX 6KPY 6KPZ 6KQ0
• Descriptor: Sodium/potassium-transporting ATPase subunit alpha-1, Sodium/potassium-transporting ATPase subunit beta-1, FXYD domain-containing ion transport regulator, ... (10 entities in total)
• Functional Keywords: na+, k+-atpase, membrane protein, ion transport, cardiotonic steroids, transport protein
• Biological source: Sus scrofa (Pig); More
• Total number of polymer chains: 3
• Total formula weight: 163651.81

Authors

Kanai, R.,Cornelius, F.,Ogawa, H.,Motoyama, K.,Vilsen, B.,Toyoshima, C. (deposition date: 2020-10-12, release date: 2021-01-27, Last modification date: 2023-11-29)

Primary citation

Kanai, R.,Cornelius, F.,Ogawa, H.,Motoyama, K.,Vilsen, B.,Toyoshima, C.
Binding of cardiotonic steroids to Na + ,K + -ATPase in the E2P state.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: The 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 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.

PubMed: 33318128
DOI: 10.1073/pnas.2020438118

Experimental method

X-RAY DIFFRACTION (3.9 Å)