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6pai

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Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to RBM39 and sulfonamide E7820

Structural highlights

6pai is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DCA15_HUMAN May be involved in ubiquitination and degradation through a DBB1-CUL4 E3 protein-ubiquitin ligase.^[1]

Publication Abstract from PubMed

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 alpha1 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.

Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820.,Du X, Volkov OA, Czerwinski RM, Tan H, Huerta C, Morton ER, Rizzi JP, Wehn PM, Xu R, Nijhawan D, Wallace EM Structure. 2019 Nov 5;27(11):1625-1633.e3. doi: 10.1016/j.str.2019.10.005. PMID:31693911^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006 Sep 1;23(5):709-21. PMID:16949367 doi:http://dx.doi.org/S1097-2765(06)00570-3
↑ Du X, Volkov OA, Czerwinski RM, Tan H, Huerta C, Morton ER, Rizzi JP, Wehn PM, Xu R, Nijhawan D, Wallace EM. Structural Basis and Kinetic Pathway of RBM39 Recruitment to DCAF15 by a Sulfonamide Molecular Glue E7820. Structure. 2019 Nov 5;27(11):1625-1633.e3. doi: 10.1016/j.str.2019.10.005. PMID:31693911 doi:http://dx.doi.org/10.1016/j.str.2019.10.005