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Published on: June 9, 2023
Three-Dimensional Modeling of Thyroid Hormone Metabolites Binding to the Cancer-Relevant αvβ3 Integrin: In-Silico
Dror Tobi1,2, Eilon Krashin3,4, Paul J Davis5,6
1Department of Molecular Biology, Ariel University, Ariel, Israel.
Background:
Thyroid 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.
Methods:
In-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.
Results:
All 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'.
Summary:
Three-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.
Insights
Thyroid hormone metabolites bind to the αvβ3 integrin receptor, with sulfated forms showing the highest affinity. This binding interaction is influenced by chemical modifications like deamination and decarboxylation, impacting their cellular effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Thyroid hormones (TH) like T4 and T3 promote cancer cell growth by binding to the αvβ3 integrin receptor.
- The deaminated analogue, tetrac, inhibits TH binding to αvβ3 integrin.
- A comprehensive analysis of TH metabolite binding to αvβ3 integrin is lacking.
Purpose of the Study:
- To computationally analyze the binding affinity of various thyroid hormone metabolites to the αvβ3 integrin receptor.
- To elucidate the structural basis for differential binding energies among TH metabolites.
- To understand the potential impact of endogenous TH metabolites on integrin-mediated pathways.
Main Methods:
- In-silico molecular docking of 26 thyroid hormone metabolites to the αvβ3 integrin receptor using DOCK6.
- Calculation of binding energies using Grid score and Amber score with a distance movable region protocol.
- Inclusion of linear and cyclic RGD peptides as references due to proximity to the TH binding site.
Main Results:
- All tested TH metabolites exhibited negative free energy, indicating affinity for αvβ3 integrin.
- Sulfated T4 (T4S) and 3,3' T2 (3,3' T2S) showed the highest binding affinity, surpassing cyclic RGD.
- Decarboxylation and deamination generally reduced binding affinity, while reverse forms (e.g., 5' T3 isomers) demonstrated increased affinity.
Conclusions:
- Thyroid hormone metabolites display varying affinities for the αvβ3 integrin receptor.
- Structural modifications significantly influence TH metabolite binding to αvβ3 integrin.
- Endogenous TH metabolites may play a role in integrin-mediated cellular processes in both normal physiology and cancer.
