4ret: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ret]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RET FirstGlance]. <br> | <table><tr><td colspan='2'>[[4ret]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RET FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=17F:O-[(S)-({(2R)-2,3-BIS[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL}OXY)(HYDROXY)PHOSPHORYL]-L-SERINE'>17F</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=DGX:DIGOXIN'>DGX</scene>, <scene name='pdbligand=FRU:FRUCTOSE'>FRU</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PHD:ASPARTYL+PHOSPHATE'>PHD</scene>, <scene name='pdbligand=PRD_900003:sucrose'>PRD_900003</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=17F:O-[(S)-({(2R)-2,3-BIS[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL}OXY)(HYDROXY)PHOSPHORYL]-L-SERINE'>17F</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=DGX:DIGOXIN'>DGX</scene>, <scene name='pdbligand=FRU:FRUCTOSE'>FRU</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PHD:ASPARTYL+PHOSPHATE'>PHD</scene>, <scene name='pdbligand=PRD_900003:sucrose'>PRD_900003</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ret FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ret OCA], [https://pdbe.org/4ret PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ret RCSB], [https://www.ebi.ac.uk/pdbsum/4ret PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ret ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ret FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ret OCA], [https://pdbe.org/4ret PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ret RCSB], [https://www.ebi.ac.uk/pdbsum/4ret PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ret ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 20:49, 20 September 2023
Crystal structure of the Na,K-ATPase E2P-digoxin complex with bound magnesiumCrystal structure of the Na,K-ATPase E2P-digoxin complex with bound magnesium
Structural highlights
FunctionPublication Abstract from PubMedCardiotonic 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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