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PROTAC & Molecular Glue Ternary Complexes

  • VHL-Cullin2

    3.6 Å

  • CRBN-DDB1

    3.0 Å

  • CRBN-DDB1

    3.1 Å

Proteolysis Targeting Chimera (PROTAC)

The proteolysis targeting chimera (PROTAC) is a targeted protein degradation technology that utilizes small-molecule compounds to regulate protein levels【1】. PROTACs exhibit a distinct mode of action compared to traditional small-molecule drugs. They exploit a unique target-recognition strategy to deliver proteins to the proteasome, achieving chemical knock-down of the target protein【2-3】. These heterobifunctional molecules possess two terminal domains: one binds a specific E3 ubiquitin ligase, while the other binds a target protein of interest (POI). These domains are connected via a synthetic linker. This configuration facilitates ubiquitination of the target protein, leading to its subsequent degradation【4】.

Molecular Glue

Molecular glues are a class of small chemical molecules that act at protein-protein interaction interfaces. Together with PROTACs, they constitute targeted protein degradation technologies. Their distinction from PROTACs lies in being monofunctional small-molecule compounds【5】. Molecular glues interact with diverse and often difficult-to-predict target proteins. They induce and enhance the interaction between two proteins, ultimately mediating the ubiquitination and degradation of the target protein【6】. Like PROTAC technology, molecular glues have also become a hot topic in innovative drug discovery research.

Significance and Current Landscape

Targeted protein degradation holds immense potential for treating tumors, infectious diseases, inflammation, neurodegenerative diseases, and more, offering a breakthrough for addressing "undruggable" targets. Currently, the use of molecular glues or PROTACs to induce targeted protein degradation has sparked widespread research interest, accompanied by an exponential growth in related research publications and patents. These approaches have become favored strategies in novel drug discovery. Multiple pharmaceutical companies are now actively developing therapies in this field to address unmet clinical needs.

References

【1】An S, Fu L. Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs[J]. EBioMedicine, 2018, 36: 553-562.
【2】Neklesa T K, Winkler J D, Crews C M. Targeted protein degradation by PROTACs[J]. Pharmacology & therapeutics, 2017, 174: 138-144.
【3】Gadd M S, Testa A, Lucas X, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation[J]. Nature chemical biology, 2017, 13(5): 514-521.
【4】Sakamoto K M, Kim K B, Kumagai A, et al. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation[J]. Proceedings of the National Academy of Sciences, 2001, 98(15): 8554-8559.
【5】Simonetta K R, Taygerly J, Boyle K, et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction[J]. Nature communications, 2019, 10(1): 1402.
【6】den Besten W, Lipford J R. Prospecting for molecular glues[J]. Nature chemical biology, 2020, 16(11): 1157-1158.

Single Particle Analysis (SPA)

Cryo-EM Structure Gallery

Single Particle Analysis