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Journal of Virology, February 2006, p. 1204-1213, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1204-1213.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Paramyxovirus Receptor-Binding Molecules: Engagement of One Site on the Hemagglutinin-Neuraminidase Protein Modulates Activity at the Second Site

Matteo Porotto,1 Micaela Fornabaio,2 Olga Greengard,3 Matthew T. Murrell,4 Glen E. Kellogg,2 and Anne Moscona1*

Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, 515 East 71st St., Box 309, New York, New York 10021,1 Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Box 980540, Virginia Commonwealth University, Richmond, Virginia 23298,2 Mount Sinai School of Medicine, Department of Pediatrics, New York, New York 10029,3 Mount Sinai School of Medicine, New York, New York 100294

Received 19 August 2005/ Accepted 4 November 2005

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.

* Corresponding author. Mailing address: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, 515 East 71st St., Box 309, New York, NY 10021. Phone: (212) 746-4801. Fax: (212) 746-8261. E-mail: anm2047{at}med.cornell.edu.

Journal of Virology, February 2006, p. 1204-1213, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1204-1213.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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