4lau: Difference between revisions
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==Crystal structure of human AR complexed with NADP+ and {2-[(4-bromobenzyl)carbamoyl]-5-chlorophenoxy}acetic acid== | ==Crystal structure of human AR complexed with NADP+ and {2-[(4-bromobenzyl)carbamoyl]-5-chlorophenoxy}acetic acid== | ||
<StructureSection load='4lau' size='340' side='right' caption='[[4lau]], [[Resolution|resolution]] 0.84Å' scene=''> | <StructureSection load='4lau' size='340' side='right' caption='[[4lau]], [[Resolution|resolution]] 0.84Å' scene=''> | ||
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1B1, ALDR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1B1, ALDR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] </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=4lau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lau OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lau RCSB], [http://www.ebi.ac.uk/pdbsum/4lau 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=4lau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lau OCA], [http://pdbe.org/4lau PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lau RCSB], [http://www.ebi.ac.uk/pdbsum/4lau PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lau ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4lau" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aldose Reductase|Aldose Reductase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 06:47, 5 August 2016
Crystal structure of human AR complexed with NADP+ and {2-[(4-bromobenzyl)carbamoyl]-5-chlorophenoxy}acetic acidCrystal structure of human AR complexed with NADP+ and {2-[(4-bromobenzyl)carbamoyl]-5-chlorophenoxy}acetic acid
Structural highlights
Function[ALDR_HUMAN] Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies. Publication Abstract from PubMedIn this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes. Modulation of aldose reductase inhibition by halogen bond tuning.,Fanfrlik J, Kolar M, Kamlar M, Hurny D, Ruiz FX, Cousido-Siah A, Mitschler A, Rezac J, Munusamy E, Lepsik M, Matejicek P, Vesely J, Podjarny A, Hobza P ACS Chem Biol. 2013 Nov 15;8(11):2484-92. doi: 10.1021/cb400526n. Epub 2013 Sep, 17. PMID:23988122[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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