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Insights into the human glycan receptor conformation of 1918 pandemic hemagglutinin-glycan complexes derived from nuclear magnetic resonance and molecular dynamics studies

DOI: 10.1021/bi500338r DOI Help
PMID: 24878075 PMID Help

Authors: Stefano Elli (Istituto di Ricerche Chimiche e Biochimiche) , Eleonora Macchi (Istituto di Ricerche Chimiche e Biochimiche) , Timothy R. Rudd (Diamond Light Source) , Rahul Raman (Koch Institute of Integrative Cancer Research) , Guillherme Sassaki (Universidade Federal do Paraná) , Karthik Viswanathan (Koch Institute of Integrative Cancer Research) , Edwin Yates (University of Liverpool) , Zachary Shriver (Koch Institute of Integrative Cancer Research) , Annamaria Naggi (Istituto di Ricerche Chimiche e Biochimiche) , Giangiacomo Torri (Istituto di Ricerche Chimiche e Biochimiche) , Ram Sasisekharan (Koch Institute of Integrative Cancer Research) , Marco Guerrini (Istituto di Ricerche Chimiche e Biochimiche)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemistry , VOL 53 , PAGES 4122 - 4135

State: Published (Approved)
Published: July 2014

Open Access Open Access

Abstract: The glycan receptor binding and specificity of influenza A viral hemagglutinin (HA) are critical for virus infection and transmission in humans. However, ambiguities in the interpretation of the receptor binding specificity of hemagglutinin from human- and avian-adapted viruses have prevented an understanding of its relationship with aerosol transmissibility, an exclusive property of human-adapted viruses. A previous conformational study, which we performed, indicated that human and avian receptors sample distinct conformations in solution. On the basis of detailed nuclear magnetic resonance (NMR) studies provided herein, we offer evidence of the distinct structural constraints imposed by hemagglutinin receptor binding sites on the glycan conformational space upon binding. The hemagglutinin from the SC18 virus, which has efficient aerosol transmissibility in humans (human-adapted), imposed the most stringent constraints on the conformational space of the human glycan receptor (LSTc), compared to single (NY18) or double (AV18) amino acid HA mutants, a property correlating to the ligand–HA binding strength. This relationship was also observed for the avian-adapted HA, where the high affinity binding partner, AV18, imposed the most stringent conformational constraints on the avian receptor, compared to those imposed by NY18. In particular, it is interesting to observe how different HAs when binding to human or avian glycosidic receptors impose significantly different conformational states, in terms of the states sampled by the glycosidic backbone and/or the entire molecule shape (linear or bent), when compared to the corresponding unbound glycans. Significantly, we delineate a “characteristic NMR signature” for the human adapted hemagglutinin (SC18) binding to human glycan receptors. Therefore, the conformational space constraints imposed by the hemagglutinin receptor binding site provide a characteristic signature that could be a useful tool for the surveillance of human adaptation of other (such as H7N9 and H5N1) deadly influenza viruses.

Diamond Keywords: Influenza; Viruses

Subject Areas: Chemistry, Biology and Bio-materials


Technical Areas:

Added On: 01/02/2016 16:11

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Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Life Sciences & Biotech

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