7TE8

CA14-CBD-DB21 ternary complex

Summary for 7TE8

• Entry DOI: 10.2210/pdb7te8/pdb
• Descriptor: CA14, DB21, cannabidiol, ... (4 entities in total)
• Functional Keywords: nanobody, cannabidiol, sensor, molecular glue, biosynthetic protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 53548.94

Authors

Cao, S.,Zheng, N. (deposition date: 2022-01-04, release date: 2022-01-12, Last modification date: 2024-11-13)

Primary citation

Cao, S.,Kang, S.,Mao, H.,Yao, J.,Gu, L.,Zheng, N.
Defining molecular glues with a dual-nanobody cannabidiol sensor.
Nat Commun, 13:815-815, 2022

PubMed 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 CRL4 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.

PubMed: 35145136
DOI: 10.1038/s41467-022-28507-1

Experimental method

X-RAY DIFFRACTION (1.998 Å)