Abstract
Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa-2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors.
Highlights
The plasma membrane is one of the defining characteristics of all eukaryotic cells
Clathrin-mediated endocytosis (CME) is the specific process of material uptake using clathrin-coated vesicles (CCV) which arise from the assembly of clathrin-coated pits (CCPs)
To validate the global docking approach used with 1, Piststop®-1 was docked into the clathrin terminal domain (CTD) using the same parameters with >47% of the predicted poses clustered co-localizing with the clathrin-box binding site identified by co-crystallization (Supporting Information, Figure S1)
Summary
The plasma membrane is one of the defining characteristics of all eukaryotic cells. It serves as the boundary between the cellular components and the extracellular environment and facilitates control of cellular material ingress and egress for cells. Clathrin-mediated endocytosis (CME) is one of the major processes that regulate selective internalization of important membrane lipids, membranebound proteins, hormones and other crucial cellular cargo. These cargo include ion channels, synaptic vesicle and nutrient and growth factor receptors. CME is the specific process of material uptake using clathrin-coated vesicles (CCV) which arise from the assembly of clathrin-coated pits (CCPs). While in principle structurally simple, no total synthesis has been reported This in part is most likely a function of the difficulty in accessing the (4S,4aS,8aS)-3methylene-4,8,8a-trimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene scaffold. We report on our efforts to determine the binding site and potential modes of interaction for 1 in the clathrin terminal domain
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
