4lau: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
''' | ==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=''> | |||
== Structural highlights == | |||
[[4lau]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LAU OCA]. <br> | |||
<b>Related:</b> [[1us0|1us0]], [[2iki|2iki]], [[4laz|4laz]], [[4lb3|4lb3]], [[4lb4|4lb4]], [[4lbr|4lbr]], [[4lbs|4lbs]]<br> | |||
<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br> | |||
== 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<ref>PMID:23988122</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aldehyde reductase]] | |||
[[Category: Cousido-Siah, A.]] | |||
[[Category: Fanfrlik, J.]] | |||
[[Category: Hobza, P.]] | |||
[[Category: Kolar, M.]] | |||
[[Category: Mitschler, A.]] | |||
[[Category: Podjarny, A.]] | |||
[[Category: Ruiz, F X.]] | |||
[[Category: Cytosolic]] | |||
[[Category: Diabetes]] | |||
[[Category: Halogenated compound]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Tim barrel]] | |||
Revision as of 10:48, 30 April 2014
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 highlights4lau is a 1 chain structure. Full crystallographic information is available from OCA. Related: 1us0, 2iki, 4laz, 4lb3, 4lb4, 4lbr, 4lbs 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
|
| ||||||||||