Bachelor of Science, Kutztown University Of Pennsylvania (2013)
PhD, Pennsylvania State University College of Medicine, Biomedical Sciences (2019)
Georgios Skiniotis, Postdoctoral Faculty Sponsor
The oxytocin signaling complex reveals a molecular switch for cation dependence.
Nature structural & molecular biology
Oxytocin (OT) and vasopressin (AVP) are conserved peptide signaling hormones that are critical for diverse processes including osmotic homeostasis, reproduction, lactation and social interaction. OT acts through the oxytocin receptor (OTR), a magnesium-dependent G protein-coupled receptor that is a therapeutic target for treatment of postpartum hemorrhage, dysfunctional labor and autism. However, the molecular mechanisms that underlie OTR activation by OT and the dependence on magnesium remain unknown. Here we present the wild-type active-state structure of human OTR bound to OT and miniGq/i determined by cryo-EM. The structure reveals a unique activation mechanism adopted by OTR involving both the formation of a Mg2+ coordination complex between OT and the receptor, and disruption of transmembrane helix 7 (TM7) by OT. Our functional assays demonstrate the role of TM7 disruption and provide the mechanism of full agonism by OT and partial agonism by OT analogs. Furthermore, we find that the identity of a single cation-coordinating residue across vasopressin family receptors determines whether the receptor is cation-dependent. Collectively, these results demonstrate how the Mg2+-dependent OTR is activated by OT, provide essential information for structure-based drug discovery efforts and shed light on the molecular determinants of cation dependence of vasopressin family receptors throughout the animal kingdom.
View details for DOI 10.1038/s41594-022-00728-4
View details for PubMedID 35241813
A key amino acid in STIM1 mediates coupling to gate the Orai1 channel
CELL PRESS. 2022: 374A
View details for Web of Science ID 000759523002373
G-protein activation by a metabotropic glutamate receptor.
Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric Gi. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound Gi can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.
View details for DOI 10.1038/s41586-021-03680-3
View details for PubMedID 34194039