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| | ==Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2,6-difluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid== | | ==Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2,6-difluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid== |
| - | <StructureSection load='4lbr' size='340' side='right' caption='[[4lbr]], [[Resolution|resolution]] 0.80Å' scene=''> | + | <StructureSection load='4lbr' size='340' side='right'caption='[[4lbr]], [[Resolution|resolution]] 0.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4lbr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LBR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LBR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4lbr]] 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=4LBR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LBR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4O9:{5-CHLORO-2-[(2,6-DIFLUORO-4-IODOBENZYL)CARBAMOYL]PHENOXY}ACETIC+ACID'>4O9</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4O9:{5-CHLORO-2-[(2,6-DIFLUORO-4-IODOBENZYL)CARBAMOYL]PHENOXY}ACETIC+ACID'>4O9</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1us0|1us0]], [[2iki|2iki]], [[4lau|4lau]], [[4laz|4laz]], [[4lb3|4lb3]], [[4lb4|4lb4]], [[4lbs|4lbs]]</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=4lbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lbr OCA], [https://pdbe.org/4lbr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lbr RCSB], [https://www.ebi.ac.uk/pdbsum/4lbr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lbr ProSAT]</span></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='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=4lbr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lbr OCA], [http://pdbe.org/4lbr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lbr RCSB], [http://www.ebi.ac.uk/pdbsum/4lbr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lbr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ALDR_HUMAN 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. | + | [https://www.uniprot.org/uniprot/ALDR_HUMAN 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4lbr" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4lbr" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aldose reductase 3D structures|Aldose reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aldehyde reductase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Cousido-Siah, A]] | + | [[Category: Cousido-Siah A]] |
| - | [[Category: Fanfrlik, J]] | + | [[Category: Fanfrlik J]] |
| - | [[Category: Hobza, P]] | + | [[Category: Hobza P]] |
| - | [[Category: Kolar, M]] | + | [[Category: Kolar M]] |
| - | [[Category: Mitschler, A]] | + | [[Category: Mitschler A]] |
| - | [[Category: Podjarny, A]] | + | [[Category: Podjarny A]] |
| - | [[Category: Ruiz, F X]] | + | [[Category: Ruiz FX]] |
| - | [[Category: Aldose reductase]]
| + | |
| - | [[Category: Cytosolic]]
| + | |
| - | [[Category: Diabetes]]
| + | |
| - | [[Category: Halogenated compound]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| 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 PubMed
In 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 Also
References
- ↑ 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. Modulation of aldose reductase inhibition by halogen bond tuning. ACS Chem Biol. 2013 Nov 15;8(11):2484-92. doi: 10.1021/cb400526n. Epub 2013 Sep, 17. PMID:23988122 doi:http://dx.doi.org/10.1021/cb400526n
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