Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2
Hongjie Wang1, Roma Yumul, Hua Cao
1University of Washington, Division of Medical Genetics, Seattle, Washington, USA.
Journal of Virology
|August 16, 2013
Summary
Researchers identified key mutations in adenovirus fiber knobs that alter binding to desmoglein 2 (DSG2). This work enhances understanding of adenovirus entry and has implications for developing more potent cancer therapies using engineered proteins.
Area of Science:
- Virology
- Structural Biology
- Cancer Therapeutics
Background:
- Certain human adenovirus (Ad) serotypes utilize desmoglein 2 (DSG2) as a cellular receptor.
- Structural mechanisms of Ad binding to DSG2 remain largely uncharacterized, unlike interactions with CAR and CD46.
Purpose of the Study:
- To elucidate the structural basis of Ad binding to DSG2.
- To engineer Ad variants with enhanced DSG2 binding affinity for potential therapeutic applications.
Main Methods:
- Construction and screening of random mutant libraries of Ad3 and Ad14p1 fiber knobs expressed in Escherichia coli.
- Identification of mutations affecting Ad knob-DSG2 binding affinity.
- Crystal structure analysis of a high-affinity mutant.
Main Results:
- Identified specific amino acid residues and clusters within the Ad fiber knob groove critical for DSG2 binding.
- Discovered mutations, particularly in the EF loop of Ad3 knob, that significantly increase binding affinity to DSG2 (several orders of magnitude).
- Structural analysis revealed increased flexibility in the EF loop of a high-affinity mutant.
Conclusions:
- Defined key structural determinants for Ad-DSG2 interaction.
- Demonstrated that affinity-enhanced Ad proteins (JO-1 variants) exhibit superior therapeutic potency in cancer models.
- Findings support the development of engineered adenoviruses for improved cancer therapy delivery.
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