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Paramyxovirus receptor-binding molecules: engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site.

TitleParamyxovirus receptor-binding molecules: engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site.
Publication TypeJournal Article
Year of Publication2006
AuthorsPorotto M, Fornabaio M, Greengard O, Murrell MT, Kellogg GE, Moscona A
JournalJ Virol
Date Published2006 Feb
KeywordsAntiviral Agents, Binding Sites, Cell Line, Dimerization, Enzyme Inhibitors, Guanidines, HN Protein, Humans, Models, Molecular, Neuraminidase, Newcastle disease virus, Parainfluenza Virus 3, Human, Protein Structure, Quaternary, Pyrans, Receptors, Virus, Sialic Acids, Zanamivir

The hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out three different activities: receptor binding, receptor cleaving (neuraminidase), and triggering of the fusion protein. These three discrete properties each affect the ability of HN to promote viral fusion and entry. For human parainfluenza type 3, one bifunctional site on HN can carry out both binding and neuraminidase, and the receptor mimic, zanamivir, impairs viral entry by blocking receptor binding. We report here that for Newcastle disease virus, the HN receptor avidity is increased by zanamivir, due to activation of a second site that has higher receptor avidity. Only certain receptor mimics effectively activate the second site (site II) via occupation of site I; yet without activation of this second site, binding is mediated entirely by site I. Computational modeling designed to complement the experimental approaches suggests that the potential for small molecule receptor mimics to activate site II, upon binding to site I, directly correlates with their predicted strengths of interaction with site I. Taken together, the experimental and computational data show that the molecules with the strongest interactions with site I-zanamivir and BCX 2798-lead to the activation of site II. The finding that site II, once activated, shows higher avidity for receptor than site I, suggests paradigms for further elucidating the regulation of HN's multiple functions in the viral life cycle.

Alternate JournalJ. Virol.
PubMed ID16414997
PubMed Central IDPMC1346948
Grant ListAI 31971 / AI / NIAID NIH HHS / United States
GM 71894 / GM / NIGMS NIH HHS / United States