An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors.
The ubiquitin pathway plays a critical role in regulating diverse biological processes, and its dysregulation is associated with various diseases. Therefore, it is important to have a tool that can control the ubiquitin pathway in order to improve understanding of this pathway and to develop therapeutics against relevant diseases. We found that Chicago Sky Blue 6B binds directly to the β-groove, a major interacting surface of ubiquitin. Hence, it could successfully inhibit the enzymatic activity of ubiquitin processing enzymes and the binding of ubiquitin to the CXCR4, a cell surface ubiquitin receptor. Furthermore, we demonstrated that this ubiquitin binding chemical could effectively suppress the ubiquitin induced cancer cell migration by blocking ubiquitin-CXCR4 interaction. Current results suggest that ubiquitin binding molecules can be developed as inhibitors of ubiquitin-protein interactions, which will have the value not only in unveiling the biological role of ubiquitin but also in treating related diseases.
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea.
Thanh
T
Nguyen
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea.
Minh
M
Ho
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea.
Ambarnil
A
Ghosh
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea.
Truc
T
Kim
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea.
Sun Il
SI
Yun
Department of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK. Electronic address: S.S.Lee@soton.ac.uk.
Seung Seo
SS
Lee
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746, South Korea. Electronic address: kyeongkyu@skku.edu.
Kyeong Kyu
KK
Kim
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D057809:HEK293 Cells; D006801:Humans; D018613:Microscopy, Confocal; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014343:Trypan Blue / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*
C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D025801:Ubiquitin; C009000:pontamine sky blue; D014343:Trypan Blue
CXC4 antagonist; Chicago sky blue 6B; Druggable target; Protein-protein interaction; Ubiquitin; Ubiquitin inhibitor