7x3z
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7x3z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7X3Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7X3Z FirstGlance]. <br> | <table><tr><td colspan='2'>[[7x3z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7X3Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7X3Z FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J3Z:(9BETA,13ALPHA)-3-HYDROXYESTRA-1,3,5(10)-TRIEN-17-ONE'>J3Z</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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]] 2.25Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J3Z:(9BETA,13ALPHA)-3-HYDROXYESTRA-1,3,5(10)-TRIEN-17-ONE'>J3Z</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=7x3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7x3z OCA], [https://pdbe.org/7x3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7x3z RCSB], [https://www.ebi.ac.uk/pdbsum/7x3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7x3z 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=7x3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7x3z OCA], [https://pdbe.org/7x3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7x3z RCSB], [https://www.ebi.ac.uk/pdbsum/7x3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7x3z ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Human type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1),a member of the short-chain dehydrogenase/reductase family, catalyzes the last step in the bioactivation of the most potent estrogen estradiol with high specificity and is thus involved in estrogen-dependent diseases. As an oxidoreductase, 17beta-HSD1 can utilize both triphosphate and diphosphate cofactors in reaction at the molecular level, but more specific with triphosphate cofactor. The NADPH is much higher than NADP+ in living cells leading to preliminary reduction action. The enzyme also showed substrate-induced inhibition unprecedented in other members of 17beta-HSDs. Our previous study elucidated the structural mechanism of substrate inhibition is due to the reversely bound estrone (E1) in the substrate-binding pocket of the enzyme resulting in a dead-end complex. However, the effect of the cofactor preference on the substrate inhibition of the enzyme is not yet clear. In the present study, we solved the ternary crystal structures of 17beta-HSD1 in complex with E1 and cofactor analog NAD+ . Combined with molecular dynamics simulation using the enzyme with NADH/NADPH and different oriented E1 (normally oriented, E1N; reversely oriented, E1R), such ternary structure provides a complete picture of enzyme-substrate-cofactor interactions. The results reveal that different cofactors and substrate binding mode affect the allosteric effect between the two subunits of the enzyme. And the results from MD simulations confirmed that His(221) plays a key role in the formation of dead-end complex in NADPH complex, and the absence of stable interaction between His(221) and E1R in the NADH complex should be the main reason for its lack of substrate inhibition. | Human type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1),a member of the short-chain dehydrogenase/reductase family, catalyzes the last step in the bioactivation of the most potent estrogen estradiol with high specificity and is thus involved in estrogen-dependent diseases. As an oxidoreductase, 17beta-HSD1 can utilize both triphosphate and diphosphate cofactors in reaction at the molecular level, but more specific with triphosphate cofactor. The NADPH is much higher than NADP+ in living cells leading to preliminary reduction action. The enzyme also showed substrate-induced inhibition unprecedented in other members of 17beta-HSDs. Our previous study elucidated the structural mechanism of substrate inhibition is due to the reversely bound estrone (E1) in the substrate-binding pocket of the enzyme resulting in a dead-end complex. However, the effect of the cofactor preference on the substrate inhibition of the enzyme is not yet clear. In the present study, we solved the ternary crystal structures of 17beta-HSD1 in complex with E1 and cofactor analog NAD+ . Combined with molecular dynamics simulation using the enzyme with NADH/NADPH and different oriented E1 (normally oriented, E1N; reversely oriented, E1R), such ternary structure provides a complete picture of enzyme-substrate-cofactor interactions. The results reveal that different cofactors and substrate binding mode affect the allosteric effect between the two subunits of the enzyme. And the results from MD simulations confirmed that His(221) plays a key role in the formation of dead-end complex in NADPH complex, and the absence of stable interaction between His(221) and E1R in the NADH complex should be the main reason for its lack of substrate inhibition. | ||
| - | New insights into the substrate inhibition of human 17beta-hydroxysteroid dehydrogenase type 1.,Li T, Song X, Stephen P, Yin H, Lin SX J Steroid Biochem Mol Biol. 2023 | + | New insights into the substrate inhibition of human 17beta-hydroxysteroid dehydrogenase type 1.,Li T, Song X, Stephen P, Yin H, Lin SX J Steroid Biochem Mol Biol. 2023 Apr;228:106246. doi: , 10.1016/j.jsbmb.2023.106246. Epub 2023 Jan 10. PMID:36634828<ref>PMID:36634828</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7x3z" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7x3z" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 1 complexed with estrone and NAD
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Categories: Homo sapiens | Large Structures | Li T | Lin SX | Yin H
