5C7J

CRYSTAL STRUCTURE OF NEDD4 WITH A UB VARIANT

Summary for 5C7J

• Entry DOI: 10.2210/pdb5c7j/pdb
• Related: 5C7M
• Descriptor: E3 ubiquitin-protein ligase NEDD4, Polyubiquitin-C (3 entities in total)
• Functional Keywords: ligase, ubiquitin-protein ligase, ubiquitin variant, structural genomics consortium, sgc, structural genomics, ligase-signaling protein complex, ligase/signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : P46934; Ubiquitin: Cytoplasm : P0CG48
• Total number of polymer chains: 4
• Total formula weight: 111863.22

Authors

Walker, J.R.,Hu, J.,Dong, A.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Tong, Y.,Structural Genomics Consortium (SGC) (deposition date: 2015-06-24, release date: 2016-03-16, Last modification date: 2023-09-27)

Primary citation

Zhang, W.,Wu, K.P.,Sartori, M.A.,Kamadurai, H.B.,Ordureau, A.,Jiang, C.,Mercredi, P.Y.,Murchie, R.,Hu, J.,Persaud, A.,Mukherjee, M.,Li, N.,Doye, A.,Walker, J.R.,Sheng, Y.,Hao, Z.,Li, Y.,Brown, K.R.,Lemichez, E.,Chen, J.,Tong, Y.,Harper, J.W.,Moffat, J.,Rotin, D.,Schulman, B.A.,Sidhu, S.S.
System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.
Mol.Cell, 62:121-136, 2016

PubMed Abstract: HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.

PubMed: 26949039
DOI: 10.1016/j.molcel.2016.02.005

Experimental method

X-RAY DIFFRACTION (3 Å)