6WY1

Crystal structure of an engineered thermostable dengue virus 2 envelope protein dimer

Summary for 6WY1

• Entry DOI: 10.2210/pdb6wy1/pdb
• Descriptor: Dengue 2 soluble recombinant envelope, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: dengue virus, envelope protein, thermostable, computational protein design, protein engineering, viral protein
• Biological source: Dengue virus 2
• Total number of polymer chains: 1
• Total formula weight: 45915.53

Authors

Kudlacek, S.T.,Lakshmanane, P.,Kuhlman, B. (deposition date: 2020-05-12, release date: 2021-11-10, Last modification date: 2024-10-23)

Primary citation

Kudlacek, S.T.,Metz, S.,Thiono, D.,Payne, A.M.,Phan, T.T.N.,Tian, S.,Forsberg, L.J.,Maguire, J.,Seim, I.,Zhang, S.,Tripathy, A.,Harrison, J.,Nicely, N.I.,Soman, S.,McCracken, M.K.,Gromowski, G.D.,Jarman, R.G.,Premkumar, L.,de Silva, A.M.,Kuhlman, B.
Designed, highly expressing, thermostable dengue virus 2 envelope protein dimers elicit quaternary epitope antibodies.
Sci Adv, 7:eabg4084-eabg4084, 2021

PubMed Abstract: Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (<100 pM) and enhance production yield by more than 50-fold. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses.

PubMed: 34652943
DOI: 10.1126/sciadv.abg4084

Experimental method

X-RAY DIFFRACTION (3.42 Å)