Massachusetts Institute of Technology research seems to show that to enter human respiratory cells, the H5N1 virus must first pick a very specific type of lock.
The study appears in the journal Nature Biotechnology.
The researchers say their discovery may help scientists better monitor changes in H5N1 - and find better ways to fight it.
Flu viruses attack by binding sugar chains, called glycans, that line the airways and lungs.
The chemical linkages between the sugar molecules in these chains differ between humans and birds.
Until now it has been assumed that bird flu viruses would be adapt to humans simply by acquiring mutations that enable them to attach to the human types.
But Dr Ram Sasisekharan and colleagues found this step depends on the shape assumed by the flexible sugar chains rather than the type of linkage.
Bird flu viruses currently require cone-shaped glycans to infect birds, so the umbrella shape found in humans has protected most of us from avian flu.
This suggests that for the H5N1 bird flu virus to become pandemic it must adapt so that it can latch onto the umbrella-shaped glycans of the human upper respiratory tract.
Dr Jeremy Berg of the National Institutes of Health which funded the work said: "Sasisekharan's team has changed our view of flu viruses and how they must adapt to infect us.
"The work may also improve our ability to monitor the evolution of the H5N1 virus and thwart potential outbreaks."
Professor Ian Jones, professor of virology at the University of Reading, said: "This new work shows that there are sublevels of sugar that the virus prefers to use to get into cells and the authors suggest this is a significant factor in why H5N1 has not yet spread to humans.
"It provides a finer level of analysis than has been done so far but it is likely that other factors, like the reduced temperate of the human upper airway, also are involved."