5l7y: Difference between revisions
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The | ==17beta-hydroxysteroid dehydrogenase 14 variant T205 in complex with a non-steroidal inhibitor.== | ||
<StructureSection load='5l7y' size='340' side='right'caption='[[5l7y]], [[Resolution|resolution]] 1.91Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5l7y]] is a 1 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=5L7Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L7Y FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.912Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6QO:(4-FLUORANYL-3-OXIDANYL-PHENYL)-[6-(2-FLUORANYL-3-OXIDANYL-PHENYL)PYRIDIN-2-YL]METHANONE'>6QO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=5l7y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l7y OCA], [https://pdbe.org/5l7y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l7y RCSB], [https://www.ebi.ac.uk/pdbsum/5l7y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l7y ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DHB14_HUMAN DHB14_HUMAN] Has NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. Converts oestradiol to oestrone. The physiological substrate is not known. Acts on oestradiol and 5-androstene-3-beta,17-beta-diol (in vitro).<ref>PMID:17067289</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
17beta-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17beta-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17beta-HSD1 and 17beta-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17beta-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17beta-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17beta-HSD1 and 17beta-HSD2 is also addressed. | |||
First Structure-Activity Relationship of 17beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.,Braun F, Bertoletti N, Moller G, Adamski J, Steinmetzer T, Salah M, Abdelsamie AS, van Koppen CJ, Heine A, Klebe G, Marchais-Oberwinkler S J Med Chem. 2016 Dec 8;59(23):10719-10737. Epub 2016 Nov 18. PMID:27933965<ref>PMID:27933965</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5l7y" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Heine | *[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bertoletti N]] | |||
[[Category: Braun F]] | |||
[[Category: Heine A]] | |||
[[Category: Klebe G]] | |||
[[Category: Marchais-Oberwinkler S]] | |||
Latest revision as of 19:10, 4 October 2023
17beta-hydroxysteroid dehydrogenase 14 variant T205 in complex with a non-steroidal inhibitor.17beta-hydroxysteroid dehydrogenase 14 variant T205 in complex with a non-steroidal inhibitor.
Structural highlights
FunctionDHB14_HUMAN Has NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. Converts oestradiol to oestrone. The physiological substrate is not known. Acts on oestradiol and 5-androstene-3-beta,17-beta-diol (in vitro).[1] Publication Abstract from PubMed17beta-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17beta-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17beta-HSD1 and 17beta-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17beta-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17beta-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17beta-HSD1 and 17beta-HSD2 is also addressed. First Structure-Activity Relationship of 17beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.,Braun F, Bertoletti N, Moller G, Adamski J, Steinmetzer T, Salah M, Abdelsamie AS, van Koppen CJ, Heine A, Klebe G, Marchais-Oberwinkler S J Med Chem. 2016 Dec 8;59(23):10719-10737. Epub 2016 Nov 18. PMID:27933965[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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