The common cold: Structural determination of HRV16, its complex with the cellular receptor ICAM-1, its implications in terms of drug design and the understanding of the virus life cycle
Abstract
Rhinoviruses, are picornaviruses, with over 100 distinct serological types, are the major cause of the common cold. These viruses comprise the largest families of human and agricultural pathogens, such as poliomyelitis, hepatitis A and meningitis. These viruses are icosahedral in shape and are made up of sixty copies of four viral proteins VP1, VP2, VP3 and an internal protein associated with the RNA, VP4. Surrounding the fivefold axes of the icosahedra is a 12 A deep depression or canyon. This depression was proposed to be the receptor binding site. The amino acids located at the floor of the canyon are conserved among the different serotypes of rhinovirus, and inaccessible to antibodies, while those lining the rim of the canyon are variable. The structure of the HRV16::ICAM-1(D1D2) complex has shown that the receptor binds to the deeper regions of the canyon floor as hypothesized. The results also show the identity of the amino acids that may interact with the virus. Due to the large structural similarity among different picornaviruses, they have been target for the development of antiviral agents with a broad range of activity. These antiviral agents interact with the capsid protein VP1, causing inhibition of uncoating and, in some cases, inhibition of attachment. The structural determination of HRV16 and its comparison to the other two known structures of rhinovirus, one belonging to the major receptor group (HRV14) and the other belonging to the minor receptor group (HRV1A) has revealed two surprising aspects: (1) HRV16 has great similarity with HRV1A which does not use ICAM-1 as its cellular receptor and belongs to the minor receptor group; (2) HRV16 has a putative cofactor bound to the cavity of VP1 where antiviral agents bind. The structural determination of a drug bound to HRV16 is also presented and its interactions with capsid protein are compared with those interactions observed in two other serotypes. The structures of drug resistant mutants of HRV14 are also reported. These mutants are natural variants capable of replicating in the presence of antiviral agents. The mechanism of resistance is discussed and the relationship between drug binding and receptor interaction is discussed in light of these structures.
Degree
Ph.D.
Advisors
Rossmann, Purdue University.
Subject Area
Biochemistry|Biophysics|Microbiology
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