Defining molecular glues with a dual-nanobody cannabidiol sensor

Shiyun Cao, Shoukai Kang, Haibin Mao, Jiayu Yao, Liangcai Gu and Ning Zheng ()
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Shiyun Cao: University of Washington
Shoukai Kang: University of Washington
Haibin Mao: University of Washington
Jiayu Yao: University of Washington
Liangcai Gu: University of Washington
Ning Zheng: University of Washington

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28507-1

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