The structure of coxsackievirus B3 at 3.5 å resolution

Abstract

The canyon and twofold depression, major surface depressions, are predicted to be the primary and secondary receptor-binding sites on CVB3, respectively. Neutralizing immunogenic sites are predicted to lie on the extreme surfaces of the capsid at sites that lack amino acid sequence conservation among the CVBs. The ions located on the icosahedral threefold and fivefold axes together with the pocket factor may contribute to the pH stability of the coxsackieviruses.

Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket

“…In contrast to I1092, I1207 is not involved in the formation of the binding pocket (Muckelbauer et al, 1995a). Therefore, the observation that mutation of I1207 can lead to a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 complete loss of drug action is intriguing.…”

“…In contrast to I1092, I1207 is not involved in the formation of the drug-binding pocket (Muckelbauer et al, 1995a). Therefore, the observation that mutation of I1207 can lead to a complete loss of drug action is intriguing.…”

“…Both the binding mode of pleconaril and the postulated drug resistance mechanism show similarities with oseltamivir resistance of influenza viruses caused by H274Y (Wang et al, 2002). The active site of influenza neuraminidase is highly polar In contrast to I1092, I1207 is not involved in the formation of the binding pocket (Muckelbauer et al, 1995a). Therefore, the observation that mutation of I1207 can lead to a complete loss of drug action is intriguing.…”

“…According to the definition of Heinz et al , substitutions in I1092 confer high-level resistance . This can be explained by the fact that I1092 is one of the 17 amino acids forming the hydrophobic pocket of CVB3 (Muckelbauer et al, 1995a). I1092 is situated in the center of the pocket and interacts with one of the two methyl groups of pleconaril's phenyl ring.…”

“…This pocket factor stabilizes the capsid and is released during the viral attachment, thereby facilitating viral uncoating (Rossmann et al, 2002). CIs are known to bind to this hydrophobic pocket and trigger conformational rearrangements in the viral capsid (Grant et al, 1994;Kim et al, 1993;Muckelbauer et al, 1995a;Zhang et al, 2004). Subsequently, attachment of viruses to host cells and/or uncoating is blocked .…”