Structural basis of endogenous inverse agonism and subtype selectivity at melanocortin receptors

Authors

Liu, X., Sun, Q., Zhang, S., Zhang, X., Sun, X.

Abstract

Endogenous inverse agonists suppress constitutive G protein-coupled receptor (GPCR) signaling, but their mechanisms remain poorly understood. Here we report cryo-EM structures of melanocortin-1 receptor (MC1R) bound to its endogenous inverse agonist, agouti signaling protein (ASIP) and melanocortin-4 receptor (MC4R) bound to agouti-related protein (AgRP). Together with previously reported structures and those we determined using extracellular nanobodies developed here, these data delineate a conformational continuum underlying receptor activation and silencing. Both inverse agonists occlude the orthosteric pocket as molecular corks and drive a shared TM3-centered extracellular remodeling. Against this common mechanism, subtype selectivity is encoded not by the conserved orthosteric pocket but by the divergent extracellular receptor surface, engaged through an ASIP C-terminal loop-dependent clasp. These findings establish a mechanistic framework for endogenous inverse agonism and identify the receptor periphery as a tractable target for subtype-selective modulation.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Sep 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.