posted on 2024-02-20, 11:29authored byIsabella
C. Russell, Xin Zhang, Fabian Bumbak, Samantha M. McNeill, Tracy M. Josephs, Michael G. Leeming, George Christopoulos, Hariprasad Venugopal, Maria M. Flocco, Patrick M. Sexton, Denise Wootten, Matthew J. Belousoff
The class A orphan
G protein-coupled receptor (GPCR), GPR3, has
been implicated in a variety of conditions, including Alzheimer’s
and premature ovarian failure. GPR3 constitutively couples with Gαs,
resulting in the production of cAMP in cells. While tool compounds
and several putative endogenous ligands have emerged for the receptor,
its endogenous ligand, if it exists, remains a mystery. As novel potential
drug targets, the structures of orphan GPCRs have been of increasing
interest, revealing distinct modes of activation, including autoactivation,
presence of constitutively activating mutations, or via cryptic ligands.
Here, we present a cryo-electron microscopy (cryo-EM) structure of
the orphan GPCR, GPR3 in complex with DNGαs and Gβ1γ2. The structure revealed clear density
for a lipid-like ligand that bound within an extended hydrophobic
groove, suggesting that the observed “constitutive activity”
was likely due to activation via a lipid that may be ubiquitously
present. Analysis of conformational variance within the cryo-EM data
set revealed twisting motions of the GPR3 transmembrane helices that
appeared coordinated with changes in the lipid-like density. We propose
a mechanism for the binding of a lipid to its putative orthosteric
binding pocket linked to the GPR3 dynamics.