4fal

From Proteopedia

(Difference between revisions)

Revision as of 11:19, 4 August 2016

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 3-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-methylbenzamide (80)

Structural highlights

4fal is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4fa3, 4fam
Gene:	AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[AK1C3_HUMAN] Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.

Publication Abstract from PubMed

A high-throughput screen identified 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of "reverse sulfonamides" showed a 12-fold preference for the R stereoisomer. The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay.

3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-beta-Hydroxysteroid Dehydrogenase AKR1C3.,Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA J Med Chem. 2012 Sep 13;55(17):7746-58. Epub 2012 Aug 21. PMID:22877157^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jamieson SM, Brooke DG, Heinrich D, Atwell GJ, Silva S, Hamilton EJ, Turnbull AP, Rigoreau LJ, Trivier E, Soudy C, Samlal SS, Owen PJ, Schroeder E, Raynham T, Flanagan JU, Denny WA. 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-beta-Hydroxysteroid Dehydrogenase AKR1C3. J Med Chem. 2012 Sep 13;55(17):7746-58. Epub 2012 Aug 21. PMID:22877157 doi:http://dx.doi.org/10.1021/jm3007867

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4fal"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 3-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-methylbenzamide (80)==
 <StructureSection load='4fal' size='340' side='right' caption='[[4fal]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fa3|4fa3]], [[4fam|4fam]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4fal FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fal OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fal RCSB], [http://www.ebi.ac.uk/pdbsum/4fal PDBsum]</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=4fal FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fal OCA], [http://pdbe.org/4fal PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fal RCSB], [http://www.ebi.ac.uk/pdbsum/4fal PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fal ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4fal" style="background-color:#fffaf0;"></div>
 ==See Also==

4fal

From Proteopedia

Revision as of 11:19, 4 August 2016

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 3-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-methylbenzamide (80)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox