4ret | pdb_00004ret

Crystal structure of the Na,K-ATPase E2P-digoxin complex with bound magnesium

spinqualitylabelsall models 4ret, resolution 4.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ret is a 6 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 17F, CLR, DGX, FRU, GLC, MG, NAG, PHD, PRD_900003 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q58K79_PIG Publication Abstract from PubMed Cardiotonic steroids (CTSs) are specific and potent inhibitors of the Na(+),K(+)-ATPase, with highest affinity to the phosphoenzyme (E2P) forms. CTSs are comprised of a steroid core, which can be glycosylated, and a varying number of substituents, including a five- or six-membered lactone. These functionalities have specific influence on the binding properties. We report crystal structures of the Na(+),K(+)-ATPase in the E2P form in complex with bufalin (a nonglycosylated CTS with a six-membered lactone) and digoxin (a trisaccharide-conjugated CTS with a five-membered lactone) and compare their characteristics and binding kinetics with the previously described E2P-ouabain complex to derive specific details and the general mechanism of CTS binding and inhibition. CTSs block the extracellular cation exchange pathway, and cation-binding sites I and II are differently occupied: A single Mg(2+) is bound in site II of the digoxin and ouabain complexes, whereas both sites are occupied by K(+) in the E2P-bufalin complex. In all complexes, alphaM4 adopts a wound form, characteristic for the E2P state and favorable for high-affinity CTS binding. We conclude that the occupants of the cation-binding site and the type of the lactone substituent determine the arrangement of alphaM4 and hypothesize that winding/unwinding of alphaM4 represents a trigger for high-affinity CTS binding. We find that the level of glycosylation affects the depth of CTS binding and that the steroid core substituents fine tune the configuration of transmembrane helices alphaM1-2. Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex.,Laursen M, Gregersen JL, Yatime L, Nissen P, Fedosova NU Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1755-60. doi:, 10.1073/pnas.1422997112. Epub 2015 Jan 26. PMID:25624492 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also ATPase 3D structures

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