A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

Abstract

BACKGROUND AND PURPOSEChemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G-protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high-resolution structural analyses of GPCR-ligand complexes. EXPERIMENTAL APPROACHIn this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high-resolution structural analyses of (hist)aminergic GPCR-ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular. KEY RESULTSOur investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by combining detailed analysis of crystallized or predicted protein-ligand binding modes, receptor mutation studies, and ligand structure-selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors. CONCLUSIONS AND IMPLICATIONSWe have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure-selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Yet, the H 2 receptor possesses many of the key prototypical amino acid residues common to the family A aminergic GPCRs, and homology modeling on the basis of the published H 1 receptor X-ray structure and available mutagenesis data leads to reasonable models (Fig. 2) for the interaction of histamine with the receptor protein Histamine Receptors (Kooistra et al, 2013 ). Mutation of either-alone or simultaneously-did not abolish histamine-induced cAMP but markedly reduced its efficacy.…”

“…Like for all biogenic amine receptors, the H 3 receptor contains the conserved Asp residue in TM3 (Asp114 3.32 ), which is suggested to be involved in the binding of the ethylamine side chain of histamine ( Fig. 2) (Kooistra et al, 2013 , this might also explain the substantially higher affinity of histamine for H 3 receptors (and also H 4 receptors; see Fig. 3; Tables 1 and 2) (Kooistra et al, 2013).…”

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

“…All aminergic GPCRs and some other rhodopsin-like GPCRs, e.g., opioid receptors, share the negatively charged and conserved aspartate residue (D3.32) in the transmembrane helix 3 (TM3) which was generally proposed as a key anchor for the basic moieties of aminergic ligands (Shi and Javitch 2002;Surgand et al 2006;Kooistra et al 2013). Accordingly, most dopamine D 2 receptor orthosteric ligands, including both agonists and antagonists fulfill the criteria of the classical pharmacophore model.…”

A Molecular Pharmacologist’s Guide to G Protein–Coupled Receptor Crystallography

“…The combination of molecular pharmacology and structural data provides a powerful lens to gain new insights into the mechanistic details of GPCR function. For instance, a systematic analysis of the functional data available for crystallized ligand-receptor complexes is crucial to elucidate the molecular determinants of ligand binding, including details of structure-activity relationships, which, in turn, can be used to extrapolate the available information to ligands and receptors that are related to known structures but have not yet been crystallized (Kooistra et al, 2013).…”

“…Finally, the cocrystallized doxepin (H 1 R), (R)-3-quinuclidinylbenzilate (muscarinic acetylcholine receptor M 2 [M 2 R]), and tiotropium (M 3 R) ligands share an amine, with two aromatic rings oriented in a butterfly shape (Fig. 5C), with many other H 1 R, M 2 R, and M 3 R ligands (Kooistra et al, 2013).…”