4lb3: Difference between revisions
No edit summary |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid== | ==Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid== | ||
<StructureSection load='4lb3' size='340' side='right' caption='[[4lb3]], [[Resolution|resolution]] 0.80Å' scene=''> | <StructureSection load='4lb3' size='340' side='right'caption='[[4lb3]], [[Resolution|resolution]] 0.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4lb3]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4lb3]] 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=4LB3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LB3 FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M15:{5-CHLORO-2-[(2-FLUORO-4-IODOBENZYL)CARBAMOYL]PHENOXY}ACETIC+ACID'>M15</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id=' | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lb3 OCA], [https://pdbe.org/4lb3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lb3 RCSB], [https://www.ebi.ac.uk/pdbsum/4lb3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lb3 ProSAT]</span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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 == | ||
| Line 23: | Line 21: | ||
==See Also== | ==See Also== | ||
*[[Aldose | *[[Aldose reductase 3D structures|Aldose reductase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Cousido-Siah | [[Category: Cousido-Siah A]] | ||
[[Category: Fanfrlik | [[Category: Fanfrlik J]] | ||
[[Category: Hobza | [[Category: Hobza P]] | ||
[[Category: Kolar | [[Category: Kolar M]] | ||
[[Category: Mitschler | [[Category: Mitschler A]] | ||
[[Category: Podjarny | [[Category: Podjarny A]] | ||
[[Category: Ruiz | [[Category: Ruiz FX]] | ||
Latest revision as of 19:15, 20 September 2023
Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acidCrystal structure of human AR complexed with NADP+ and {5-chloro-2-[(2-fluoro-4-iodobenzyl)carbamoyl]phenoxy}acetic acid
Structural highlights
FunctionALDR_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
|
| ||||||||||||||||||