7lyx
From Proteopedia
(Difference between revisions)
| (One intermediate revision not shown.) | |||
| Line 1: | Line 1: | ||
==Crystal structure of human CYP8B1 in complex with (S)-tioconazole== | ==Crystal structure of human CYP8B1 in complex with (S)-tioconazole== | ||
| - | <StructureSection load='7lyx' size='340' side='right'caption='[[7lyx]]' scene=''> | + | <StructureSection load='7lyx' size='340' side='right'caption='[[7lyx]], [[Resolution|resolution]] 2.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LYX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LYX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7lyx]] 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=7LYX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LYX FirstGlance]. <br> |
| - | </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=7lyx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lyx OCA], [https://pdbe.org/7lyx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lyx RCSB], [https://www.ebi.ac.uk/pdbsum/7lyx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lyx ProSAT]</span></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]] 2.6Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=YHM:(S)-Tioconazole'>YHM</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=7lyx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lyx OCA], [https://pdbe.org/7lyx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lyx RCSB], [https://www.ebi.ac.uk/pdbsum/7lyx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lyx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/CP8B1_HUMAN CP8B1_HUMAN] A cytochrome P450 monooxygenase involved in primary bile acid biosynthesis. Catalyzes the 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one, an intermediate metabolite in cholic acid biosynthesis (PubMed:10051404). Controls biliary balance of cholic acid and chenodeoxycholic acid, ultimately regulating the intestinal absorption of dietary lipids (By similarity). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH--hemoprotein reductase) (By similarity).[UniProtKB:O02766][UniProtKB:O88962]<ref>PMID:10051404</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Human cytochrome P450 8B1 (CYP8B1) is involved in conversion of cholesterol to bile acids. It hydroxylates the steroid ring at C12 to ultimately produce the bile acid cholic acid. Studies implicated this enzyme as a good drug target for nonalcoholic fatty liver disease and type 2 diabetes, but there are no selective inhibitors known for this enzyme and no structures to guide inhibitor development. Herein, the human CYP8B1 protein was generated and used to identify and characterize interactions with a series of azole inhibitors, which tend to be poorly selective P450 inhibitors. Structurally related miconazole, econazole, and tioconazole bound with submicromolar dissociation constants and were effective inhibitors of the native reaction. CYP8B was cocrystallized with S-tioconazole to yield the first X-ray structure. This inhibitor bound in the active site with its azole nitrogen coordinating the heme iron, consistent with inhibitor binding and inhibition assay data. Additionally, the CYP8B1 active site was compared with similar P450 enzymes to identify features that may facilitate the design of more selective inhibitors. Selective inhibitors should promote a better understanding of the role of CYP8B1 inhibition in normal physiology and disease states and provide a possible treatment for nonalcoholic fatty liver disease and type 2 diabetes. | ||
| + | |||
| + | The structure and characterization of human cytochrome P450 8B1 supports future drug design for nonalcoholic fatty liver disease and diabetes.,Liu J, Carlson HA, Scott EE J Biol Chem. 2022 Sep;298(9):102344. doi: 10.1016/j.jbc.2022.102344. Epub 2022 , Aug 6. PMID:35944583<ref>PMID:35944583</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7lyx" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Liu J]] | [[Category: Liu J]] | ||
[[Category: Scott EE]] | [[Category: Scott EE]] | ||
Current revision
Crystal structure of human CYP8B1 in complex with (S)-tioconazole
| |||||||||||
