4LAZ

Crystal structure of human AR complexed with NADP+ and {5-chloro-2-[(4-iodobenzyl)carbamoyl]phenoxy}acetic acid

Summary for 4LAZ

• Entry DOI: 10.2210/pdb4laz/pdb
• Related: 1US0 2IKI 4LAU 4LB3 4LB4 4LBR 4LBS
• Descriptor: Aldose reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, {5-chloro-2-[(4-iodobenzyl)carbamoyl]phenoxy}acetic acid, ... (4 entities in total)
• Functional Keywords: tim barrel, aldose reductase, oxidoreductase, diabetes, halogenated compound, cytosolic
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 1
• Total formula weight: 37087.38

Authors

Cousido-Siah, A.,Mitschler, A.,Ruiz, F.X.,Fanfrlik, J.,Kolar, M.,Hobza, P.,Podjarny, A. (deposition date: 2013-06-20, release date: 2014-04-30, Last modification date: 2023-09-20)

Primary citation

Fanfrlik, J.,Kolar, M.,Kamlar, M.,Hurny, D.,Ruiz, F.X.,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., 8:2484-2492, 2013

PubMed Abstract: 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.

PubMed: 23988122
DOI: 10.1021/cb400526n

Experimental method

X-RAY DIFFRACTION (0.85 Å)