Defining molecular glues with a dual-nanobody cannabidiol sensor

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Molecular glues (MGs) are a class of compounds that induce proximity between proteins.
• Their development has been limited by an unclear definition and thermodynamic understanding.
• Existing examples include the plant hormone auxin and synthetic protein degraders like immune-modulatory imide drugs (IMiDs).

Purpose of the Study:

• To define the molecular mechanism and thermodynamic characteristics of molecular glues.
• To establish criteria for the rational discovery of novel molecular glues.
• To differentiate molecular glues from bifunctional compounds.

Main Methods:

• Crystal structure determination of a dual-nanobody cannabidiol-sensing system.
• Quantitative analysis of protein-protein interactions.
• Comparison with auxin perception complexes and CRL4^CRBN E3 ligase.

Main Results:

• The crystal structure reveals ligand-induced protein-protein interaction analogous to auxin.
• Parallels were drawn between the cannabidiol sensor, auxin complex, and IMiD-bound CRL4^CRBN.
• A unifying feature identified is a ligand-enhanced, pre-existing low micromolar affinity between protein partners, reaching nanomolar range.

Conclusions:

• Molecular glues are defined by two key features: lack of ligand binding in one partner and ligand-enhanced weak protein-protein interactions.
• This mechanism distinguishes MGs from bifunctional compounds.
• These findings provide criteria for guiding the rational discovery of new molecular glues.