Remember, remember the 5th of November. Today marks the tenth anniversary of my PhD defense. I'm officially old now. (fin)

Huge thanks to our amazing team — and especially to my first graduate student Saif Khan (second from right), who spearheaded this project with incredible drive and creativity. Credit also goes to him for the stunning movie in the first post. (8/n)

Supported by extensive molecular dynamics simulations, we assembled the first half of the G protein activation pathway — a major step toward understanding how GPCRs translate drug binding into cellular signaling. (7/n)

The mind-blowing part: a “latent” state — where the receptor and G protein both appear inactive, yet remain bound to each other. Naloxone traps this state, stalling activation. This likely explains its ability to block opioid signaling so effectively. (6/n)

To explore this further, we determined a series of four novel GDP-bound MOR–G protein structures — the first of their kind for any GPCR. Remarkably, the distribution of these states correlated with the efficacy of the respective ligand. (5/n)

We developed a simple BRET-based assay — “nuc-BRET” — to approximate the nucleotide affinity (EC₅₀) of MOR–G protein complexes. We found a clear inverse correlation: Antagonists stabilize GDP binding, while agonists promote its release for GTP exchange. (4/n)

Recent smFRET and DEER studies from the Kobilka lab (Zhang et al. 2024 Nature; Deutsch et al. 2025 bioRxiv, etc.) revealed clear links between MOR conformations and ligand efficacy. These findings inspired our next step. (3/n)

A big research theme in our lab: how do different drugs acting on the same receptor cause different levels of activity? This concept — called efficacy — lies at the heart of receptor pharmacology and drug discovery efforts. (2/n)

μ-opioid receptors (MOR) mainly signal by activating G proteins. This happens when the G protein swaps its bound GDP molecule for GTP — triggering subunit dissociation and downstream signaling. A classic textbook cartoon, from Alberts et al. - Molecular Biology of the Cell: (1/n)