The Next Landmark in GPCR Structural Elucidation

Susan Boyd

In the beginning – a very long time ago it seems – there was bacteriorhodpsin. The only available GPCR crystal structure, upon which all early homology models were based.  Then, in 2000, along came the structure of bovine rhodopsin – the first mammalian GPCR to be crystallized.  This helped modeling a little, but let’s face it, there were still an awful lot of issues with structural modeling of GPCRs.  Then, in 2007 new technologies were utilized to stabilize GPCR structures, including binding of a monoclonal antibody to the third intracellular loop, or insertion of T4 lysozyme to constrain this flexible loop, which opened the gates to a flurry of family A GPCR structures.  A third route to GPCR stabilization was also being pioneered around this time by Heptares, whereby specific point mutations were introduced to the GPCR protein construct to thermally stabilize the protein.  In recent years, with these various technologies in hand, both agonist and antagonist-bound structures of family A GPCRs have become available, and the true complexity of the conformational states adopted by agonist, antagonist, inverse agonist and partial agonist ligands started to unfold.

Now it would seem that the next major chapter in GPCR structural elucidation is upon us, heralded by the publication of the first Family B GPCR structures in July. Structures of the glucagon receptor (PDB id 4L6R.pdb, crystallized in the presence of an antagonist, but with no ligand visible in the electron density) from a multi-national academic/industrial partnership including the Scripps Institute and Novo Nordisk(1), and the human corticotrophin-releasing factor 1 receptor structure (PDB id 4K5Y.pdb) from Heptares(2), crystallised with antagonist CP-376395, has uncovered yet more structural surprises, revealing a binding site which is substantially displaced compared with the known Family A structures.  The Family B transmembrane domain appears to be conformationally distinct from the corresponding Family A domains elucidated to date, adopting a more V-shaped shape in the Family B structures.

This is a significant step forward in our understanding of GPCR structure and function, and should provide a model for other family B structures.


Image taken from (2), showing the site of the corticotrophin-releasing factor 1 receptor structure antagonist CP-376395, compared with the antagonist binding site observed for Family A GPCR structures to date.


1. Siu, F. Y. et al. Structure of the human glucagon class B G-protein-coupled receptor. Nature 499, 444–449 (2013)

2. Hollenstein, K. et al. Structure of class B GPCR corticotropinreleasing factor receptor 1. Nature 499, 438–443 (2013)