The quest for high-resolution G protein-coupled receptor–G protein structures
Year: 2020
Type: article
Abstract: G protein-coupled receptors (GPCRs) are integral membrane proteins that mediate many responses of cells to external stimuli (1). The fundamental role of GPCRs in regulating human cellular processes makes them high-value targets for drugs (2). GPCRs are highly dynamic entities, and thus, determination of high-resolution structures of GPCRs in complex with their binding partners by X-ray crystallography or by cryoelectron microscopy (cryo-EM) techniques is a delicate experimental undertaking despite tremendous progress in recent years (3). In this issue of PNAS, Mafi et al. (4) explore an alternative approach, molecular dynamics simulations, as a means to elucidate the atomistic structure of the human κ-opioid receptor (κOR) in complex with a potent agonist and the heterotrimeric Gi protein. To obtain structural information of GPCR–agonist–G protein complexes by computational methods is a welcome addition to existing experimental techniques.
On activation by a ligand from the extracellular side, GPCRs interact with heterotrimeric G protein(s) and/or with arrestin(s) on the cytoplasmic side, initiating downstream signaling (1). A given agonist can stabilize a particular subset of receptor conformations favoring the binding of a particular G protein. Other ligands stimulate both G protein and arrestin pathways, activate multiple G proteins, or drive signaling through arrestin. The greater efficacy toward one or the other route is called ligand bias (5). The ability of some ligands to stimulate both pathways may cause undesired effects of drugs directed at GPCRs. For example, morphine acts on opioid receptors and is highly effective for pain relief …
[↵][1]1Email: reinhard.grisshammer2{at}nih.gov.
[1]: #xref-corresp-1-1
Author: Reinhard Grisshammer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3011305029