Teresa Cardote, a Ph.D. student, and Dr. Morgan Gadd, a former post-doctoral researcher in Professor Alessio Ciulli’s lab in BCDD, have had their research published in the Cell Press journal Structure. It reports a new crystal structure of a full Cullin RING E3 ligase (CRLs) complex. CRLs play important biological roles in physiology and disease, particularly in cancer, and are emerging as high-profile drug targets for the pharmaceutical industry.
“We solved the first crystal structure of the whole VHL ligase complex. It comprises the first full-length structure of Cullin-2, which is only the fourth full-length structure available of the Cullin family. Our structure unveils the protein-protein interaction between Cullin-2 and the RING subunit Rbx1, and Rbx1 presents a new conformation. We propose that the new conformation is a pose en route from the inactive to the active state of the ligase,” explained Teresa. “This new knowledge is important as CRLs are attractive targets for drug development but also for the development of inducers of targeted protein degradation (PROTACs), which provides an alternative innovative approach for developing drugs.” This work has been presented at the ZOMES IX meeting, an international conference in Rome, earlier this year.
“We were delighted to see for the first time a full picture at atomic detail of a whole Cullin-2 ligase complex!” says Professor Ciulli. “The disclosed information aids greater understanding of how these molecular machines assemble and function in cells, which underpins much of the development of targeting small molecules. The next step to better elucidate how these enzymes work will be to interrogate their dynamic movements, how chemical modifications affect them, and how they recognize other partner proteins during their cellular activity.
Teresa, a native of Portugal, is in her final year of her Ph.D. and has had a great experience while undertaking her studies here. “The School of Life Sciences (SLS) offers great facilities and easy access to a wide range of cutting edge technologies that enrich the whole learning process. The interaction between groups and researchers is one of the greatest strengths of this institute. It was also very exciting from the personal point of view, the SLS is a very friendly multicultural environment, you can meet people from everywhere in the world!” said Teresa.