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In silico study of fragile histidine triad interaction domains with MDM2 and p53
Ameneh Eslamparast1, Mohammad Hossein Ghahremani2, Soroush Sardari1
1Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
Background:
Fragile histidine triad (FHIT) is considered as a member of the histidine triad (HIT) nucleotide-binding protein superfamily regarded as a putative tumor suppressor executing crucial role in inhibiting p53 degradation by MDM2. Accumulating evidences indicate FHIT interaction with p53 or MDM2; however, there is no certain study deciphering functional domains of FHIT involving in the interaction with MDM2 and/or p53. In this regard, such evident interaction can spring in mind determining important domains of FHIT binding to MDM2 with regard to p53.
Materials And Methods:
Since there were not any previous studies appraising complete three-dimensional structures of target molecules, molecular modeling was carried out to construct three-dimensional models of full FHIT, MDM2, P53 and also FHIT segments. Truncated structures of FHIT were created to reveal critical regions engaging in FHIT interaction.
Results:
Given the shape and shape/electrostatic total energy, FHIT structures (β1-5), (β3-7, α1), and (β5-7, α1) appeared to be better candidates than other structures in interaction with full MDM2. Furthermore, FHIT structures (β6-7), (β6-7, α1), (β4-7, α1) were considered to be better than other structures in interaction with p53. FHIT truncates that interact with MDM2 presented lower energy levels than FHIT truncates interacting with p53.
Conclusion:
These findings are beneficial to understand the mechanism of the FHIT-MDM2-p53 complex activation for designing inhibitory compounds.
Insights
The fragile histidine triad (FHIT) protein interacts with MDM2 and p53. Molecular modeling identified specific FHIT domains crucial for binding MDM2 and p53, aiding in cancer therapy development.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The fragile histidine triad (FHIT) protein, a member of the histidine triad (HIT) superfamily, acts as a tumor suppressor.
- FHIT is known to inhibit p53 degradation by MDM2, but the specific domains involved in these interactions are unclear.
Purpose of the Study:
- To identify the functional domains of FHIT responsible for interacting with MDM2 and p53.
- To elucidate the structural basis of the FHIT-MDM2-p53 complex.
Main Methods:
- Utilized molecular modeling to construct 3D structures of FHIT, MDM2, and p53.
- Generated truncated FHIT structures to pinpoint critical interaction regions.
Main Results:
- Specific FHIT structures (e.g., β1-5, β3-7/α1) showed strong binding affinity with MDM2.
- Other FHIT structures (e.g., β6-7, β6-7/α1) demonstrated significant interaction with p53.
- FHIT truncates interacting with MDM2 exhibited lower energy levels compared to those interacting with p53.
Conclusions:
- Identified key FHIT domains involved in MDM2 and p53 binding.
- Findings provide a foundation for understanding the FHIT-MDM2-p53 complex.
- Results can guide the design of novel inhibitory compounds for cancer therapy.
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