Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico Based Study

Frontiers in Endocrinology

Dror Tobi²  Osnat Ashur-Fabian³  Eilon Krashin³  Vivian Cody⁶  Martin Ellis⁷  Paul J. Davis⁸ 

[1] Department of Structural Biology, SUNY, University at Buffalo, Buffalo, NY, United States;Department of Computer Sciences, Ariel University, Ariel, Israel;Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;Department of Medicine, Albany Medical College, Albany, NY, United States;Department of Molecular Biology, Ariel University, Ariel, Israel;;Hauptman-Woodward Medical Research Institute &Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel;Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, United States;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel;

关键词: thyroid hormones;    binding energy;    integrin;    affinity;    in-silico docking;   

DOI  :  10.3389/fendo.2022.895240

来源: DOAJ

【 摘 要 】

BackgroundThyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvβ3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvβ3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking.MethodsIn-silico docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvβ3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol.ResultsAll TH molecules demonstrated negative free energy, suggesting affinity to the αvβ3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3’ T2 (3,3’ T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket via divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5’.SummaryThree-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvβ3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer.

【 授权许可】

Unknown