Paramyxovirus receptor-binding molecules: engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site.
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.
Porotto
Matteo
M
Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, 515 East 71st Street, Box 309, New York, NY 10021, USA.
Fornabaio
Micaela
M
Greengard
Olga
O
Murrell
Matthew T
MT
Kellogg
Glen E
GE
Moscona
Anne
A
D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D015707:HN Protein / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009522:Newcastle disease virus / Q000235:genetics / Q000502:physiology*; D010224:Parainfluenza Virus 3, Human / Q000235:genetics / Q000502:physiology*; D020836:Protein Structure, Quaternary; D011714:Pyrans / Q000494:pharmacology; D011991:Receptors, Virus / Q000187:drug effects / Q000502:physiology*; D012794:Sialic Acids / Q000494:pharmacology; D053243:Zanamivir
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D015707:HN Protein; C039111:HN protein receptor; D011714:Pyrans; D011991:Receptors, Virus; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir