X-ray structural information of GPCRs in drug design: what are the limitations and where do we go?

INTRODUCTION: In 2007, the X-ray structural determination of non-rhodopsin G-Protein coupled receptors (GPCRs), considered the most extensively targeted protein class for marketed drugs, commenced. With the relatively rapid availability of additional structures, an assessment of the progression made is needed in addition to the assessment of the understandings gleaned, deployment successes and forthcoming prospects. AREAS COVERED: The author reviews the approaches and tools that have made it possible to determine the three dimensional structures of GPCRs using X-ray crystallography. Furthermore, the author describes the methods suited for crystallization of membrane bound GPCR proteins including the lipidic cubic phase and various protein modification approaches. The author also provides highlights, from the literature, of the structures determined to date including targets solved, the nature of the content provided (such as selectivity, activating vs. inactivating determinants) and how these structural features relate to drug design strategies. EXPERT OPINION: The GPCR X-ray structures that have been so far determined have yielded significant information. This has presented dramatic evidence concerning their ability to impact the discovery of compounds through their action as traditional, orthosteric modulators. It is, however, noted that more challenging design strategies, such as identifying biased agonists and the use of sites remote from the orthosteric site for allosteric modulation, are still in their infancy.