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Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion

2015

Proceedings of the National Academy of Sciences of the United States of America, 2015, Vol.112(7), pp.2034-2039 [Peer Reviewed Journal]

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  • Title:
    Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion
  • Is Part Of: Proceedings of the National Academy of Sciences of the United States of America, 2015, Vol.112(7), pp.2034-2039
  • Description: Alphavirus envelope proteins, organized as trimers of E2–E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.
    Significance Alphaviruses infect human cells through endocytosis and low pH-triggered membrane fusion. Because of the recent epidemics and lack of specific treatment for alphaviral infections, numerous investigations have aimed to deduce the mechanism of the alphaviral infection pathway. Building on previous structural models of the viral envelope proteins, we identify critical histidine protonation-state changes responsible for pH-triggered conformational transitions between key fusion intermediates through quantitative calculation of pK ₐ and free energies and further show that the key contributions arise from the His residues having conserved sequences and chemical environments. Our study provides insight into the mechanistic roles of these residues and suggests hotspots for targeting inhibitors that could shift the pH profile of membrane fusion and thus, interfere with infectivity. ; p. 2034-2039.
  • Publisher: National Academy of Sciences
  • Creation Date: 2015
  • Language: English
  • Identifier: ISSN: 0027-8424
  • Source: AGRIS (Food and Agriculture Organization of the United Nations)

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