Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017 Nobel Prize in Chemistry for Dubochet, Frank, and Henderson) for resolving protein structures at near atomic resolution has been highlighted as one such approach. Now some of the first papers applying this methodology to G protein-coupled receptors (GPCRs) are beginning to appear. The strength of this approach for GPCRs is revealed in the recent paper by Koehl et al. (1) showing the detailed structure of the agonist-bound µ opioid receptor (GtoPdb target ID 139) coupled to the Gi subtype of G protein. DAMGO (GtoPdb ligand ID 1647), the agonist used in the study, is a selective and efficacious peptide agonist at the µ receptor and is used in many studies as the standard µ receptor agonist. The structure of the DAMGO-µ receptor-Gi complex shows some interesting and unexpected detail, for example, that the binding pocket for Gi at the base of the receptor is smaller, and the outswing of the lower end of TMD VI smaller, than that for GPCRs that couple primarily to Gs proteins.
Apart from the obvious benefits for future drug development at µ receptor, the full impact of the cryo-EM approach for µ receptor structure/function is likely to be felt more in the future, as we can no doubt look forward to the appearance of µ receptor/signalling protein structures with partial agonists as well as biased agonists, and the structure of ligand-bound µ receptor interacting with GRKs or arrestin proteins. The speed at which this field is moving is already breathtaking – in the issue of Nature carrying the DAMGO-µ receptor-Gi cryo-EM report, there are others detailing the structure of activated rhodopsin-Gi (2), adenosine activated adenosine A1-Gi (3) and agonist-activated 5HT1B-Go (4). Recently also the structure of the Class B GLP-1 receptor in complex with a biased ligand and Gs was reported (5). Many more structures of such complexes are likely to follow over the next couple of years, with a corresponding leap forward in our understanding of the structure and function of GPCRs. There are still challenges however; as Koehl and colleagues point out in their groundbreaking paper (1), the nature of the initial interactions of G proteins and other signalling proteins with GPCRs, and the identity of the possibly novel receptor conformations that exist at these early time points in complex formation, remain considerable challenges for both X-ray crystallography and cryo-EM techniques.
Comments by Eamonn Kelly (E.Kelly@bristol.ac.uk) and Katy Sutcliffe
(1) Koehl A. et al. (2018). Structure of the μ-opioid receptor–Gi protein complex. Nature, 558. 547–552. [PMID: 29899455]
(2) Kang Y. et al. (2018). Cryo-EM structure of human rhodopsin bound to an inhibitory G protein. Nature, 558. 553-558. [PMID: 29899450]
(3) Draper-Joyce C.J. et al. (2018). Structure of the adenosine-bound human adenosine A1 receptor–Gi complex. Nature, 558. 559–563. [PMID: 29925945]
(4) García-Nafría J. et al. (2018). Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go. Nature, 558. 620-623. [PMID: 29925951]
(5) Liang Y.L. et al. (2018). Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature, 555. 121-125. [PMID: 29466332]
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