Details

Autor(en) / Beteiligte

• Du, Xinlin
• Volkov, Oleg A.
• Czerwinski, Robert M.
• Tan, HuiLing
• Huerta, Carlos
• Morton, Emily R.
• Rizzi, Jim P.
• Wehn, Paul M.
• Xu, Rui
• Nijhawan, Deepak
• Wallace, Eli M.

Titel

Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820

Ist Teil von

• Structure (London), 2019-11, Vol.27 (11), p.1625-1633.e3

Ort / Verlag

United States: Elsevier Ltd

Erscheinungsjahr

2019

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest. [Display omitted] •DCAF15-sulfonamide binds to RBM39 through a single α helix of RBM39•The structure reveals how a sulfonamide molecular glue recruits RBM39 to DCAF15•Both RBM39 and E7820 have weak affinity to DCAF15 individually•Synergistic binding to DCAF15 leads to the formation of stable ternary complex Du et al. describe in structural and kinetic detail how a sulfonamide glue, E7820, recruits RBM39 to DCAF15, a CUL4-related E3 ubiquitin ligase. RBM39 and E7820 each has weak affinity to DCAF15; however, synergistic binding of the two to DCAF15 leads to the formation of a stable ternary complex.