Nat commu: three dimensional structure of protein reveals new mechanism of anticancer drugs

February 17, 2019 / bioin / - ubiquitin (UB) and ubiquitin like modifiers (Ubls) will be activated in the first step of the cascade reaction of E1 enzyme activating ubiquitin like modifiers (Ubls), so it is a potential target of therapeutic interventions for cancer and other fatal diseases Photo source: nature communications recently from Medical University of South Carolina Carolina, musc) reported the crystal structure of E1 enzyme when it forms a complex with a recently discovered coh000, a highly specific covalent structure inhibitor This 3D structure allows researchers to observe the interaction between potential drug molecules and target proteins The researchers found that coh000 would target a mysterious pocket far away from the active site, which has been ignored in all previous studies on the structure of SUMO E1 At the same time, the process of combining coh000 with SUMO E1 was completed through a series of structural changes, and finally the enzyme was fixed in an inactive conformational state that had not been found before These structural changes include the disassembly of one active site and the 180 ° rotation of the catalytic SCCH domain containing cysteine "We're learning the secrets of nature - how these molecules work, and we're doing it in a way that we can see By studying these processes at the molecular level, we can make full use of them " Shaun Olsen, lead author of the study and associate professor of biology and molecular biology at musc, said In general, this study provides a molecular basis for the inhibition mechanism of cou000 and its sumo E1 specificity, and also provides a new direction for the development of molecules targeting the mysterious allosteric site of E1 enzyme The researchers' next plan is to use these three-dimensional structures to design inhibitors with stronger specificity and anticancer activity Reference: Zongyang LV et al, molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating envelope, nature communications (2018) Doi: 10.1038/s41467-018-07015-1