4lb3: Difference between revisions
No edit summary |
No edit summary |
||
| Line 2: | Line 2: | ||
<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. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LB3 OCA]. <br> | <table><tr><td colspan='2'>[[4lb3]] 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=4LB3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LB3 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1us0|1us0]], [[2iki|2iki]], [[4lau|4lau]], [[4laz|4laz]], [[4lb4|4lb4]], [[4lbr|4lbr]], [[4lbs|4lbs]]</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]], [[4lb4|4lb4]], [[4lbr|4lbr]], [[4lbs|4lbs]]</td></tr> | ||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/ | <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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lb3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lb3 RCSB], [http://www.ebi.ac.uk/pdbsum/4lb3 PDBsum]</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> | ||
<table> | <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=4lb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lb3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lb3 RCSB], [http://www.ebi.ac.uk/pdbsum/4lb3 PDBsum]</span></td></tr> | ||
</table> | |||
== 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. | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 14: | Line 17: | ||
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<ref>PMID:23988122</ref> | 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<ref>PMID:23988122</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
== References == | == References == | ||
| Line 21: | Line 24: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Aldehyde reductase]] | [[Category: Aldehyde reductase]] | ||
[[Category: Cousido-Siah, A | [[Category: Human]] | ||
[[Category: Fanfrlik, J | [[Category: Cousido-Siah, A]] | ||
[[Category: Hobza, P | [[Category: Fanfrlik, J]] | ||
[[Category: Kolar, M | [[Category: Hobza, P]] | ||
[[Category: Mitschler, A | [[Category: Kolar, M]] | ||
[[Category: Podjarny, A | [[Category: Mitschler, A]] | ||
[[Category: Ruiz, F X | [[Category: Podjarny, A]] | ||
[[Category: Ruiz, F X]] | |||
[[Category: Aldose reductase]] | [[Category: Aldose reductase]] | ||
[[Category: Cytosolic]] | [[Category: Cytosolic]] | ||
Revision as of 22:25, 25 December 2014
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
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. References
|
| ||||||||||||||||||||||