In silico study of fragile histidine triad interaction domains with MDM2 and p53.
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ABSTRACT: 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 (?1-5), (?3-7, ?1), and (?5-7, ?1) appeared to be better candidates than other structures in interaction with full MDM2. Furthermore, FHIT structures (?6-7), (?6-7, ?1), (?4-7, ?1) 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.
SUBMITTER: Eslamparast A
PROVIDER: S-EPMC4162077 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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