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A. The Canyon
Page 491
The HRVs have been divided into the major and minor receptor groups based on two identified cellular
receptors [3]. The major group, which is comprised of approximately 90 serotypes, binds to the
intercellular adhesion molecule 1 (ICAM-1) [20]. The minor group, about 10 serotypes, binds to the low
density lipoprotein receptor family [21].
The canyons are depressions approximately 15 to 20 Å deep that encircle each icosahedral five-fold axis
(Figure 1). When first seen in HRV 14, these canyons were postulated to be the site at which a cellular
receptor would bind. Subsequent electron-microscopic data revealed that ICAM-1 does indeed bind in
the canyon as predicted, although in a somewhat different orientation than early models [22,23]. These
canyons allow the receptor binding sites to escape immunological surveillance because the canyons are
too narrow to allow an immunoglobulin to contact the canyon floor. Directly underneath the floor of the
canyon lies a second important structure, the VP1 hydrophobic pocket.
B. The VP1 Hydrophobic Pocket
The VP1 hydrophobic pocket is the site where the capsid-binding compounds reside. This hydrophobic
pocket in VP1 was not initially apparent in the HRV14 structure because it exists in a closed
conformation in the native HRV14. The addition of a capsid-binding antiviral agent induces the pocket
to open. This was first seen by Smith and coworkers when the first crystal structure of a capsid-binding
drug, WIN 51711, was solved bound in HRV14 [24]. (WIN is the designation for a Sterling Winthrop
compound.) This was a seminal event in the structure-based design of these capsid-binding compounds;
before this structure was solved the exact site at which the compounds bound was unknown.
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