4hx5: Difference between revisions
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== | ==Crystal structure of 11 beta-HSD1 in complex with SAR184841== | ||
[[http://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN | <StructureSection load='4hx5' size='340' side='right'caption='[[4hx5]], [[Resolution|resolution]] 2.19Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4hx5]] is a 4 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=4HX5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HX5 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]] 2.19Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19V:4-[5-(4-TERT-BUTYLPIPERAZIN-1-YL)PYRIDIN-2-YL]-N-[(1R,2S,3S,5S,7S)-5-CARBAMOYLTRICYCLO[3.3.1.1~3,7~]DEC-2-YL]-3,4-DIHYDROQUINOXALINE-1(2H)-CARBOXAMIDE'>19V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=4hx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hx5 OCA], [https://pdbe.org/4hx5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hx5 RCSB], [https://www.ebi.ac.uk/pdbsum/4hx5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hx5 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Defects in HSD11B1 are a cause of cortisone reductase deficiency (CRD) [MIM:[https://omim.org/entry/604931 604931]. In CRD, activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS). | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DHI1_HUMAN DHI1_HUMAN] Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7-ketocholesterol to 7-beta-hydroxycholesterol (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Starting from 11beta-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11beta-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes. | |||
Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D.,Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faihun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Farjot G, Noah L, Maniani K, Boutarfa A, Nicolai E, Guillot E, Pruniaux MP, Gussregen S, Engel C, Coutant AL, de Miguel B, Castro A Bioorg Med Chem Lett. 2013 Apr 15;23(8):2414-21. doi: 10.1016/j.bmcl.2013.02.018., Epub 2013 Feb 22. PMID:23478147<ref>PMID:23478147</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[ | <div class="pdbe-citations 4hx5" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Hydroxysteroid dehydrogenase 3D structures|Hydroxysteroid dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Engel CK]] | ||
[[Category: | [[Category: Loenze P]] | ||
[[Category: | [[Category: Schimanski-Breves S]] | ||
Latest revision as of 15:12, 20 September 2023
Crystal structure of 11 beta-HSD1 in complex with SAR184841
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