Big congratulations to @kelseyperson.bsky.social and @valeriarobleto.bsky.social on receiving SfN Trainee Professional Development Awards. 🎉 So grateful to @sfn.org for this support!

Lots of cool stuff going on. Come to visit, and stay to get your fill of dose-response curves and learn more than you ever (knew you) wanted to know about neurotensin receptor 1!! 🤓 📈

🎉 thanks @jwietek.bsky.social!!

Thank you Nina!!

Thanks Ben!!

Thank you, Tom!!

Yay! Really psyched for the team here. Thank you, Zoe!!

Led by superstar students @kelseyperson.bsky.social and Maddi Moore with @valeriarobleto.bsky.social. This entire line of investigation was made possible by Steve Olson and his med chem group @sbpdiscovery.bsky.social. Hugely grateful to our entire team at UMN and beyond!

Why are we excited? This is a strategy for changing the cellular consequences of receptor activation and achieving truly biased, G protein-subtype-selective compounds that is broadly applicable to the GPCR superfamily. So many new possibilities!

These data suggest that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the GPCR-transducer interface.

Differences in the G protein selectivity profiles of these new modulators were probe-independent, conserved across receptor species, and translated to differences in in vivo activity - efficacy in a rodent model of NTSR1 agonist-induced hypothermia.

Other compounds produced surprising results indicating that some G protein C-termini can also adopt a third, distinct conformation in the presence of a stabilizing modulator. WHAT. 🤯

Remarkably, small modifications to the SBI-553 scaffold produce compounds with qualitatively different G protein activation profiles! Some compounds behaved as predicted – like this one 🎳

Can this compound’s G protein selectivity profile be changed by modifying its structure? Yes! Based on these models, we compiled a series of SBI-553 derivatives and screened them in a high-dimensional SAR study including representative G protein family members and β-arrestin.

G protein homology models based on this alternative, shallow-binding conformation did a great job at explaining SBI-553’s G protein subtype-specific effects on NT and its own agonism.

Why does this work? The G protein C-terminus needs to adopt a new binding position to accommodate the compound. SBI-553 blocks G protein binding determinants, promoting association with select G protein subtypes for which a shallow-binding conformation is energetically favorable.

If not through β-arrestin, where does the block come from? Subtype-selective steric exclusion. Sensitivity to SBI-553 antagonism is determined by the primary structure of the G protein C-terminus and can be changed by swapping just the 5 C-term amino acids of these G proteins.