Structure and receptor binding of the hemagglutinin from a human H6N1 influenza virus

Netanel Tzarum, Robert P. De Vries, Xueyong Zhu, Wenli Yu, Ryan McBride, James C. Paulson*, Ian A. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Avian influenza viruses that cause infection and are transmissible in humans involve changes in the receptor binding site (RBS) of the viral hemagglutinin (HA) that alter receptor preference from α2-3-linked (avian-like) to α2-6-linked (human-like) sialosides. A human case of avian-origin H6N1 influenza virus was recently reported, but the molecular mechanisms contributing to it crossing the species barrier are unknown. We find that, although the H6 HA RBS contains D190V and G228S substitutions that potentially promote human receptor binding, recombinant H6 HA preferentially binds α2-3-linked sialosides, indicating no adaptation to human receptors. Crystal structures of H6 HA with avian and human receptor analogs reveal that H6 HA preferentially interacts with avian receptor analogs. This binding mechanism differs from other HA subtypes due to a unique combination of RBS residues, highlighting additional variation in HA-receptor interactions and the challenges in predicting which influenza strains and subtypes can infect humans and cause pandemics.

Original languageAmerican English
Pages (from-to)369-376
Number of pages8
JournalCell Host and Microbe
Issue number3
StatePublished - 11 Mar 2015
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded in part by National Institutes of Health Grants R56 AI099275 (to I.A.W.) and AI099274 (to J.C.P.). R.P.d.V. is a recipient of a Rubicon and Veni grants from the Netherlands Organization for Scientific Research (NWO) . We thank R. Stanfield, X. Dai, and M. Elsliger for crystallographic and computational support; H. Tien of the Robotics Core at the Joint Center for Structural Genomics for automated crystal screening (supported by NIH Grant U54 GM094586 ); the staff at APS beamline 23ID-B (GM/CA CAT); and SSRL beamlines 11-1 and 12-2. GM/CA CAT is funded in whole or in part with federal funds from the National Cancer Institute ( Y1-CO-1020 ) and NIGMS ( Y1-GM-1104 ). Use of the Advanced Photon Source was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science , under contract number DE-AC02-06CH11357 . The SSRL is a Directorate of Stanford Linear Accelerator Center National Accelerator Laboratory and an Office of Science User Facility operated for the U.S. DOE Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, NIGMS (including P41GM103393 ), and the National Center for Research Resources (NCRR, P41RR001209 ). This is manuscript 28035 from The Scripps Research Institute.

Publisher Copyright:
© 2015 Elsevier Inc.


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