Summary for 4RES
| Entry DOI | 10.2210/pdb4res/pdb |
| Related | 3N23 4HYT 4RET |
| Related PRD ID | PRD_900003 |
| Descriptor | Sodium/potassium-transporting ATPase subunit alpha-1, 2-acetamido-2-deoxy-beta-D-glucopyranose, O-[(S)-({(2R)-2,3-bis[(9Z)-octadec-9-enoyloxy]propyl}oxy)(hydroxy)phosphoryl]-L-serine, ... (11 entities in total) |
| Functional Keywords | alpha-helical transmembrane protein, atpase, sodium ion transport, potassium ion transport, atp binding, sodium binding, potassium binding, receptor for cardiotonic steroids, phosphorylation, glycosylation, plasma membrane, multisubunit complex, trimeric complex, membrane protein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Sus scrofa (pig) More |
| Total number of polymer chains | 6 |
| Total formula weight | 314299.96 |
| Authors | Laursen, M.,Yatime, L.,Gregersen, J.L.,Nissen, P.,Fedosova, N.U. (deposition date: 2014-09-23, release date: 2015-01-28, Last modification date: 2023-09-20) |
| Primary citation | Laursen, M.,Gregersen, J.L.,Yatime, L.,Nissen, P.,Fedosova, N.U. Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex. Proc.Natl.Acad.Sci.USA, 112:1755-1760, 2015 Cited by PubMed Abstract: 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, αM4 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 αM4 and hypothesize that winding/unwinding of αM4 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 αM1-2. PubMed: 25624492DOI: 10.1073/pnas.1422997112 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.408 Å) |
Structure validation
Download full validation report
