|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5l7t' size='340' side='right'caption='[[5l7t]], [[Resolution|resolution]] 1.98Å' scene=''> | | <StructureSection load='5l7t' size='340' side='right'caption='[[5l7t]], [[Resolution|resolution]] 1.98Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5l7t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L7T OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5L7T FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5l7t]] 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=5L7T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L7T FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6QJ:(4-FLUORANYL-3-OXIDANYL-PHENYL)-[6-(3-METHYL-4-OXIDANYL-PHENYL)PYRIDIN-2-YL]METHANONE'>6QJ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.983Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSD17B14, DHRS10, SDR3, SDR47C1, UNQ502/PRO474 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6QJ:(4-FLUORANYL-3-OXIDANYL-PHENYL)-[6-(3-METHYL-4-OXIDANYL-PHENYL)PYRIDIN-2-YL]METHANONE'>6QJ</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'>[http://proteopedia.org/fgij/fg.htm?mol=5l7t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l7t OCA], [http://pdbe.org/5l7t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l7t RCSB], [http://www.ebi.ac.uk/pdbsum/5l7t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l7t 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=5l7t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l7t OCA], [https://pdbe.org/5l7t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l7t RCSB], [https://www.ebi.ac.uk/pdbsum/5l7t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l7t ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 26: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bertoletti, N]] | + | [[Category: Bertoletti N]] |
| - | [[Category: Braun, F]] | + | [[Category: Braun F]] |
| - | [[Category: Heine, A]] | + | [[Category: Heine A]] |
| - | [[Category: Klebe, G]] | + | [[Category: Klebe G]] |
| - | [[Category: Marchais-Oberwinkler, S]] | + | [[Category: Marchais-Oberwinkler S]] |
| - | [[Category: Hydroxysteroid dehydrogenase]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
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).[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lukacik P, Keller B, Bunkoczi G, Kavanagh KL, Lee WH, Adamski J, Oppermann U. Structural and biochemical characterization of human orphan DHRS10 reveals a novel cytosolic enzyme with steroid dehydrogenase activity. Biochem J. 2007 Mar 15;402(3):419-27. PMID:17067289 doi:BJ20061319
- ↑ Braun F, Bertoletti N, Moller G, Adamski J, Steinmetzer T, Salah M, Abdelsamie AS, van Koppen CJ, Heine A, Klebe G, Marchais-Oberwinkler S. First Structure-Activity Relationship of 17beta-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme. J Med Chem. 2016 Dec 8;59(23):10719-10737. Epub 2016 Nov 18. PMID:27933965 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01436
|
