8dbz | pdb_00008dbz
CryoEM structure of Hantavirus ANDV Gn(H) protein complex with 2Fabs ANDV-5 and ANDV-34
Structural highlights
FunctionGP_ANDV Forms homotetramers with glycoprotein C at the surface of the virion (By similarity). Attaches the virion to host cell receptors including integrin ITGAV/ITGB3 (By similarity). This attachment induces virion internalization possibly through clathrin-dependent endocytosis and dynamin-independent macropinocytosis (Probable). Mediates the assembly and budding of infectious virus particles through its interaction with the nucleocapsid protein and the viral genome (By similarity). May dysregulate normal immune and endothelial cell responses through an ITAM motif (By similarity). Translocates to mitochondria, binds to host TUFM and recruits MAP1LC3B (By similarity). These interactions induce mitochondrial autophagy and therefore destruction of host MAVS leading to inhibition of type I interferon (IFN) responses (By similarity). Concomitant breakdown of glycoprotein N is apparently prevented by the nucleoprotein that may inhibit Gn-stimulated autophagosome-lysosome fusion (By similarity). Interacts with the viral genomic RNA (By similarity). Inhibits the host RIG-I/TBK1 pathway by disrupting the formation of TBK1-TRAF3 complexes and downstream signaling responses required for IFN-beta transcription (PubMed:24390324, PubMed:16973572).[UniProtKB:P08668][UniProtKB:P27312][1] [2] Forms homotetramers with glycoprotein N at the surface of the virion. Attaches the virion to host cell receptors including integrin ITGAV/ITGB3. This attachment induces virion internalization predominantly through clathrin-dependent endocytosis (By similarity). Class II fusion protein that promotes fusion of viral membrane with host endosomal membrane after endocytosis of the virion (PubMed:31180319, PubMed:27414047).[UniProtKB:P08668][3] [4] Publication Abstract from PubMedHantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While infections in humans are relatively rare, mortality rates range from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the human humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity to authentic hantaviruses. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines. Antigenic mapping and functional characterization of human new world hantavirus neutralizing antibodies.,Engdahl TB, Binshtein E, Brocato RL, Kuzmina NA, Principe LM, Kwilas SA, Kim RK, Chapman NS, Porter MS, Guardado-Calvo P, Rey FA, Handal LS, Diaz SM, Zagol-Ikapitte IA, Tran MH, McDonald WH, Meiler J, Reidy JX, Trivette A, Bukreyev A, Hooper JW, Crowe JE Jr Elife. 2023 Mar 27;12:e81743. doi: 10.7554/eLife.81743. PMID:36971354[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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