Unifying family A GPCR theories of activation.

Several new pairs of active and inactive GPCR structures have recently been solved enabling detailed structural insight into the activation process, not only of rhodopsin but now also of the β2 adrenergic, M2 muscarinic and adenosine A2A receptors. Combined with structural analyses they have enabled us to examine the different recent theories proposed for GPCR activation and show that they are all indeed parts of the same process, and are intrinsically related through their effect on the central hydrophobic core of GPCRs. This new unifying general process of activation is consistent with the identification of known constitutively active mutants and an in-depth conservational analysis of significant residues implicated in the process.

Modeling active GPCR conformations.

The most significant advance in modeling GPCR active states has been the β(2)-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding.

G-protein-coupled receptor dynamics: dimerization and activation models compared with experiment.

Our previously derived models of the active state of the β2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). These molecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The β2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures.

Modeling GPCR active state conformations: the β(2)-adrenergic receptor.

The recent publication of several G protein-coupled receptor (GPCR) structures has increased the information available for homology modeling inactive class A GPCRs. Moreover, the opsin crystal structure shows some active features. We have therefore combined information from these two sources to generate an extensively validated model of the active conformation of the β(2)-adrenergic receptor.

1,2,4-Triazolyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists.

The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.