4LIY

Structure of the adenovirus 3 knob domain K217E and F224S mutant

Summary for 4LIY

• Entry DOI: 10.2210/pdb4liy/pdb
• Related: 1H7Z
• Descriptor: Fiber protein, SULFATE ION (3 entities in total)
• Functional Keywords: adenovirus fibre protein knob domain, viral attachment to host cell, receptor interaction, desmoglein 2, viral protein
• Biological source: Human adenovirus 3 (HAdV-3)
• Cellular location: Virion (By similarity): P04501
• Total number of polymer chains: 3
• Total formula weight: 83563.25

Authors

Zubieta, C.,Fender, P. (deposition date: 2013-07-04, release date: 2014-05-28, Last modification date: 2023-11-08)

Primary citation

Wang, H.,Yumul, R.,Cao, H.,Ran, L.,Fan, X.,Richter, M.,Epstein, F.,Gralow, J.,Zubieta, C.,Fender, P.,Lieber, A.
Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2
J.Virol., 87:11346-11362, 2013

PubMed Abstract: Human adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14, as well as a recently emerged strain of Ad14 (Ad14p1), use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. Unlike Ad interaction with CAR and CD46, structural details for Ad binding to DSG2 are still elusive. Using an approach based on Escherichia coli expression libraries of random Ad3 and Ad14p1 fiber knob mutants, we identified amino acid residues that, when mutated individually, ablated or reduced Ad knob binding to DSG2. These residues formed three clusters inside one groove at the extreme distal end of the fiber knob. The Ad3 fiber knob mutant library was also used to identify variants with increased affinity to DSG2. We found a number of mutations within or near the EF loop of the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than those to the wild-type Ad3 knob. Crystal structure analysis of one of the mutants showed that the introduced mutations make the EF loop more flexible, which might facilitate the interaction with DSG2. Our findings have practical relevance for cancer therapy. We have recently reported that an Ad3 fiber knob-containing recombinant protein (JO-1) is able to trigger opening of junctions between epithelial cancer cells which, in turn, greatly improved the intratumoral penetration and efficacy of therapeutic agents (I. Beyer, et al., Clin. Cancer Res. 18:3340-3351, 2012; I. Beyer, et al., Cancer Res. 71:7080-7090, 2011). Here, we show that affinity-enhanced versions of JO-1 are therapeutically more potent than the parental protein in a series of cancer models.

PubMed: 23946456
DOI: 10.1128/JVI.01825-13

Experimental method

X-RAY DIFFRACTION (2.1 Å)