3nty: Difference between revisions
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[[ | ==Crystal structure of AKR1C1 in complex with NADP and 5-Phenyl,3-chlorosalicylic acid== | ||
<StructureSection load='3nty' size='340' side='right' caption='[[3nty]], [[Resolution|resolution]] 1.87Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3nty]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NTY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NTY FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5P3:5-CHLORO-4-HYDROXYBIPHENYL-3-CARBOXYLIC+ACID'>5P3</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=3nty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nty OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3nty RCSB], [http://www.ebi.ac.uk/pdbsum/3nty PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) is an important drug target due to its role in the development of lung and endometrial cancers, premature birth and neuronal disorders. We report the crystal structure of AKR1C1 complexed with the first structure-based designed inhibitor 3-chloro-5-phenylsalicylic acid (K(i)=0.86nM) bound in the active site. The binding of 3-chloro-5-phenylsalicylic acid to AKR1C1 resulted in a conformational change in the side chain of Phe311 to accommodate the bulky phenyl ring substituent at the 5-position of the inhibitor. The contributions of the nonconserved residues Leu54, Leu306, Leu308 and Phe311 to the binding were further investigated by site-directed mutagenesis, and the effects of the mutations on the K(i) value were determined. The Leu54Val and Leu306Ala mutations resulted in 6- and 81-fold increases, respectively, in K(i) values compared to the wild-type enzyme, while the remaining mutations had little or no effects. | |||
Probing the inhibitor selectivity pocket of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) with X-ray crystallography and site-directed mutagenesis.,El-Kabbani O, Dhagat U, Soda M, Endo S, Matsunaga T, Hara A Bioorg Med Chem Lett. 2011 Apr 15;21(8):2564-7. Epub 2011 Jan 22. PMID:21414777<ref>PMID:21414777</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]] | *[[Hydroxysteroid dehydrogenase|Hydroxysteroid dehydrogenase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Dhagat, U | [[Category: Dhagat, U]] | ||
[[Category: El-Kabbani, O | [[Category: El-Kabbani, O]] | ||
[[Category: 20 alpha hydroxysteroid dehydrogenase]] | [[Category: 20 alpha hydroxysteroid dehydrogenase]] | ||
[[Category: Akr1c1]] | [[Category: Akr1c1]] | ||
[[Category: Aldo-keto reductase]] | [[Category: Aldo-keto reductase]] | ||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
Revision as of 15:30, 9 December 2014
Crystal structure of AKR1C1 in complex with NADP and 5-Phenyl,3-chlorosalicylic acidCrystal structure of AKR1C1 in complex with NADP and 5-Phenyl,3-chlorosalicylic acid
Structural highlights
Publication Abstract from PubMedHuman 20alpha-hydroxysteroid dehydrogenase (AKR1C1) is an important drug target due to its role in the development of lung and endometrial cancers, premature birth and neuronal disorders. We report the crystal structure of AKR1C1 complexed with the first structure-based designed inhibitor 3-chloro-5-phenylsalicylic acid (K(i)=0.86nM) bound in the active site. The binding of 3-chloro-5-phenylsalicylic acid to AKR1C1 resulted in a conformational change in the side chain of Phe311 to accommodate the bulky phenyl ring substituent at the 5-position of the inhibitor. The contributions of the nonconserved residues Leu54, Leu306, Leu308 and Phe311 to the binding were further investigated by site-directed mutagenesis, and the effects of the mutations on the K(i) value were determined. The Leu54Val and Leu306Ala mutations resulted in 6- and 81-fold increases, respectively, in K(i) values compared to the wild-type enzyme, while the remaining mutations had little or no effects. Probing the inhibitor selectivity pocket of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) with X-ray crystallography and site-directed mutagenesis.,El-Kabbani O, Dhagat U, Soda M, Endo S, Matsunaga T, Hara A Bioorg Med Chem Lett. 2011 Apr 15;21(8):2564-7. Epub 2011 Jan 22. PMID:21414777[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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