Command Palette

Search for a command to run...

Preprint WatchMildSeptember 5th, 2026

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

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

Cryo-EM structures of MC1R bound to agouti signalling protein and MC4R bound to agouti-related protein explain how endogenous inverse agonists suppress constitutive melanocortin receptor signalling and how subtype selectivity arises.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint reports cryo-EM structures of MC1R bound to its endogenous inverse agonist agouti signalling protein, together with MC4R bound to agouti-related protein, and uses them to explain how endogenous inverse agonists suppress constitutive melanocortin receptor signalling and how subtype selectivity is achieved. The Claidex graph holds one MC1R record, ac225-a9-3408-mc1r-metastatic-melanoma-phase1-strategic-termination, a Phase 1 targeted alpha therapy terminated for portfolio reasons rather than for any mechanistic result. The flag is mild because that failure carries no efficacy or safety verdict against MC1R, and because structural work on constitutive signalling and subtype selectivity is directly useful for ligand design in MC1R directed delivery. Anyone building on these structures should note that the only clinical MC1R record in the graph closed before producing an interpretable readout.

Abstract excerpt

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.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.