6cgc: Difference between revisions
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==Crystal structure of human 17beta-HSD type 1 in ternary complex with 2-MeO-CC-156 and NADP+== | |||
<StructureSection load='6cgc' size='340' side='right' caption='[[6cgc]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6cgc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CGC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CGC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F0A:3-{[(9beta,14beta,16alpha,17alpha)-3,17-dihydroxy-2-methoxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide'>F0A</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/17-beta-estradiol_17-dehydrogenase 17-beta-estradiol 17-dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.62 1.1.1.62] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cgc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cgc OCA], [http://pdbe.org/6cgc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cgc RCSB], [http://www.ebi.ac.uk/pdbsum/6cgc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cgc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/DHB1_HUMAN DHB1_HUMAN]] Favors the reduction of estrogens and androgens. Also has 20-alpha-HSD activity. Uses preferentially NADH. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the progression of estrogen-related diseases because of its involvement in the biosynthesis of estradiol (E2), constituting a valuable therapeutic target for endocrine treatment. In the present study, we successfully cocrystallized the enzyme with the reversible inhibitor 2-methoxy-16beta-( m-carbamoylbenzyl)-E2 (2-MeO-CC-156) as well as the enzyme with the irreversible inhibitor 3-(2-bromoethyl)-16beta-( m-carbamoylbenzyl)-17beta-hydroxy-1,3,5(10)-estratriene (PBRM). The structures of ternary complexes of 17beta-HSD1-2-MeO-CC-156-NADP(+) and 17beta-HSD1-PBRM-NADP(+) comparatively show the formation of a covalent bond between His(221) and the bromoethyl side chain of the inhibitor in the PBRM structure. A dynamic process including beneficial molecular interactions that favor the specific binding of a low-reactivity inhibitor and subsequent N-alkylation event through the participation of His(221) in the enzyme catalytic site clearly demonstrates the covalent bond formation. This finding opens the door to a new design of alkyl halide-based specific covalent inhibitors as potential therapeutic agents for different enzymes, contributing to the development of highly efficient inhibitors. | |||
Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide.,Li T, Maltais R, Poirier D, Lin SX J Phys Chem Lett. 2018 Sep 20;9(18):5275-5280. doi: 10.1021/acs.jpclett.8b02225. , Epub 2018 Aug 31. PMID:30148957<ref>PMID:30148957</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 6cgc" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 17-beta-estradiol 17-dehydrogenase]] | |||
[[Category: Li, T]] | [[Category: Li, T]] | ||
[[Category: Lin, S X]] | |||
[[Category: Complex]] | |||
[[Category: Hydroxysteroid dehydrogenase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 12:04, 16 January 2019
Crystal structure of human 17beta-HSD type 1 in ternary complex with 2-MeO-CC-156 and NADP+
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