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Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.

ABSTRACT: G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the beta(2) adrenergic receptor (beta(2)AR) is one of the most extensively studied. Previously, the X-ray crystal structure of beta(2)AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational differences, we determined the crystal structures of a previously described engineered beta(2)AR construct in complex with two inverse agonists: ICI 118,551 (2.8 A), a recently described compound (2.8 A) (Kolb et al, 2009), and the antagonist alprenolol (3.1 A). The structures show the same overall fold observed for the previous beta(2)AR structures and demonstrate that the ligand binding site can accommodate compounds of different chemical and pharmacological properties with only minor local structural rearrangements. All three compounds contain a hydroxy-amine motif that establishes a conserved hydrogen bond network with the receptor and chemically diverse aromatic moieties that form distinct interactions with beta(2)AR. Furthermore, receptor ligand cross-docking experiments revealed that a single beta(2)AR complex can be suitable for docking of a range of antagonists and inverse agonists but also indicate that additional ligand-receptor structures may be useful to further improve performance for in-silico docking or lead-optimization in drug design.

SUBMITTER: Wacker D

PROVIDER: S-EPMC2923663 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.

Wacker Daniel D Fenalti Gustavo G Brown Monica A MA Katritch Vsevolod V Abagyan Ruben R Cherezov Vadim V Stevens Raymond C RC

Journal of the American Chemical Society 20100801 33

G protein-coupled receptors (GPCRs) represent a large fraction of current pharmaceutical targets, and of the GPCRs, the beta(2) adrenergic receptor (beta(2)AR) is one of the most extensively studied. Previously, the X-ray crystal structure of beta(2)AR has been determined in complex with two partial inverse agonists, but the global impact of additional ligands on the structure or local impacts on the binding site are not well-understood. To assess the extent of such ligand-induced conformational ...[more]

PMID: 20669948

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Project description:Since estrogen-related receptor alpha (ERRα), one of three estrogen-related receptors, displays constitutively active transcriptional activities and important implications in both physiological and pathological processes of breast cancers, ERRα was recently recognized as a new target to fight breast cancers, and regulating the activity of ERRα with inverse agonists has thus become a promising new therapeutic strategy. A few inverse agonists cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound 1), thiadiazoacrylamide (XCT790), and 1-(2,5-diethoxy-benzyl)-3-phenyl-area analogues (compounds 2 and 3) were reported to be capable of targeting ERRα. However, the detailed mechanism by which the inverse agonists deactivate ERRα remains unclear, especially in the aspects of quantitative binding and hot spot residues. Therefore, to gain insights into the interaction modes between inverse agonists and ERRα ligand binding domain, all-atom molecular dynamics (MD) simulations were firstly carried out for the complexes of inverse agonists and ERRα. The binding free energies were then calculated with MM-PBSA method to quantitatively discuss the binding of the inverse agonists with ERRα. The binding affinities were finally decomposed to per-residue contributions to identify the hot spot residues as well as assess their role in the binding mechanism. MD simulations show that the inverse agonists stretch downwards into the ERRα ligand binding pocket (LBP) formed by H3 and H11 helices, and upon the binding H12 adopts a well-defined position in the coactivator groove, where PGC-1α binds to ERRα. Binding energy analysis indicates that compound 3 and XCT790 bind more tightly to ERRα than compounds 1 and 2, and the energy difference mainly results from the contribution of van der Waals interaction. Both binding mode analysis and affinity decomposition per-residue indicate that compound 1, XCT790, and compound 3 have similar binding spectra to ERRα, primarily interacting with the residues of H3, H5, H6/H7 loop, and H11 helix, while compound 2 lacks a significant interaction with the H5 region. The hot spot residues significantly binding to the three inverse agonists in common include Leu324, Phe328, Phe382, Leu398, Phe495, and Leu500. It is essential for an effective inverse agonist to strongly bind with the aromatic ring cluster consisting of Phe328(H3), Phe495(H11), and Phe382(H5/H6 loop) as well as Leu500.

Dataset Information

Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.

Publications

Conserved binding mode of human beta2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography.

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