Structure and Modeling of GPCRs: Implications for Drug Discovery

Diversity and modularity of G protein-coupled receptor structures

“…the 16-residue cyclic peptide antagonist CVX15 [16], can induce some substantial deviations in the side chains and helices (compare Figure 5D and E), however such deviations are usually minor for small drug-like compounds. This result has a major implication for the applicability of GPCR crystal structures to rational drug discovery [39, 40], suggesting that one (or very few) conformations of the receptor can effectively explain binding of majority of drug-like compounds. Applicability of the high-resolution GPCR structures to drug discovery has been further corroborated by retrospective Virtual Ligand Screening (VLS) (e.g.…”

The GPCR Network: a large-scale collaboration to determine human GPCR structure and function

“…Therefore, an important activity of the GPCR Network is to leverage the impact of each experimental structure towards filling gaps in understanding the structures of related GPCRs, their specificity and other functional features. This goal is being achieved through comparative analysis, as well as homology-based modeling of structures and their complexes 5, 6 (Figure 3), which has previously proven successful in applications to other major protein families 7 .…”

“…For example, prior to our collaboration which resulted in the first detailed structure of the receptor at 2.4 Å resolution, Brian Kobilka worked for approximately 20 years to study details of β 2 AR and his insight into the biochemistry of the receptor was critical, including the protein engineering and understanding of receptor pharmacology. Adriaan IJzerman and Ken Jacobson had each spent over 20 years studying the adenosine receptors before the start of our collaborations, which yielded structures of A 2A AR in complexes with an antagonist at 2.6 Å resolution 5 and an agonist at 2.8 Å resolution 19 . Quickly following the publication of the first A 2A AR structure, we worked with Ad Ijzerman, Laura Heitman and their colleagues on a careful site specific mutagenesis of the receptor binding site 20 and then with Ken Jacobson and colleagues at the NIH on the design and synthesis of novel ligands that bind the receptor 21 .…”

GPCR agonist binding revealed by modeling and crystallography

“…GPCRs can be activated by endogenous or synthetic agonists, inhibited by antagonists and inverse agonists, or affected by allosteric modulators [4], and each of these classes of ligands is therapeutically relevant. The crystal structures of β-adrenergic (β 2 AR and β 1 AR)[5–8], adenosine A 2A (A 2A AR)[9], chemokine CXCR4 [10], dopamine D3 (D3R) [11], and most recently histamine H1 (H1R)[12] receptors in complex with stabilizing antagonists provide a long sought 3D structural framework for studies of GPCR function and future drug discovery efforts ([13, 14]). Over the last few years, applicability of docking and virtual ligand screening (VLS) technologies to GPCR crystal structures [15–18] has been validated by co-crystallization of some of these ligands [8] and prospective identifications of novel β 2 AR and A 2A AR antagonist chemotypes [19–23].…”