In silico study of fragile histidine triad interaction domains with MDM2 and p53


1 Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

2 Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, 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.


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