Abstract
“Molecular glue” (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders exemplified by immune-modulatory imide drugs (IMiDs). Prospective development of MGs, however, has been hampered by its elusive definition and thermodynamic characteristics. Here, we report the crystal structure of a dual-nanobody cannabidiol-sensing system, in which the ligand promotes protein-protein interaction in a manner analogous to auxin. Through quantitative analyses, we draw close parallels among the dual-nanobody cannabidiol sensor, the auxin perception complex, and the IMiDs-bound CRL4CRBN E3, which can bind and ubiquitinate “neo-substrates”. All three systems, including the recruitment of IKZF1 and CK1α to CRBN, are characterized by the lack of ligand binding activity in at least one protein partner and an under-appreciated preexisting low micromolar affinity between the two proteinaceous subunits that is enhanced by the ligand to reach the nanomolar range. These two unifying features define MGs as a special class of proximity inducers distinct from bifunctional compounds and can be used as criteria to guide target selection for future rational discovery of MGs.
Highlights
“Molecular glue” (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders exemplified by immune-modulatory imide drugs (IMiDs)
Bifunctional molecules with two distinct chemical moieties connected by a linker can be prospectively developed to induce spatial proximity between two proteins[2,4]. Such a strategy is widely adopted for developing proteolysis targeting chimeras (PROTACs), which promote targeted protein polyubiquitination and degradation by bridging a preselected target protein to a ubiquitin ligase[5,6]
Six years after PROTACs was introduced by Deshaies and colleagues in 20015, we raised the concept of “molecular glue” (MG) to explain the mechanism of action of the master plant hormone, auxin, which is distinct from PROTACs and allosteric switches[7]
Summary
“Molecular glue” (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders exemplified by immune-modulatory imide drugs (IMiDs). The mechanism of action of auxin is recapitulated by the therapeutic compound, thalidomide, and its derivatives, such as lenalidomide and pomalidomide These compounds, collectively known as immunomodulatory drugs (IMiDs), can promote the degradation of a host of cellular proteins by extending the subpar interfaces they form with CRBN, the substrate receptor of the CUL4-RBX1-DDB1 (CRL4) ubiquitin ligase complex[9,10,11,12,13,14,15,16,17,18,19,20]. By comparing it with the auxin and IMiDs systems, we outline the common thermodynamic characteristics of the three systems that differentiate MGs from other type of proximity inducers
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