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4EKF: Structure of the Inactive Adenovirus Proteinase at 0.98 Angstrom Resolution
Regulation of a Viral Proteinase by a Peptide and DNA in One-dimensional Space: III. ATOMIC RESOLUTION STRUCTURE OF THE NASCENT FORM OF THE ADENOVIRUS PROTEINASE
J. Biol. Chem. (2013) 288 p.2081-2091» All references (8)
The adenovirus proteinase (AVP), the first member of a new class of cysteine proteinases, is essential for the production of infectious virus, and here we report its structure at 0.98 A resolution. AVP, initially synthesized as an inactive enzyme, requires two cofactors for maximal activity: pVIc, an 11-amino acid peptide, and the viral DNA. Comparison of the structure of AVP with that of an active form, the AVP-pVIc complex, reveals why AVP is inactive. Both forms have an alpha + beta fold; the major structural differences between them lie in the beta-sheet domain. In AVP-pVIc, the general base His-54 Ndelta1 is 3.9 A away from the Cys-122 Sgamma, thereby rendering it nucleophilic. In AVP, however, His-54 Ndelta1 is 7.0 A away from Cys-122 Sgamma, too far away to be able to abstract the proton from Cys-122. In AVP-pVIc, Tyr-84 forms a cation-pi interaction with His-54 that should raise the pK(a) of His-54 and freeze the imidazole ring in the place optimal for forming an ion pair with Cys-122. In AVP, however, Tyr-84 is more than 11 A away from its position in AVP-pVIc. Based on the structural differences between AVP and AVP-pVIc, we present a model that postulates that activation of AVP by pVIc occurs via a 62-amino acid-long activation pathway in which the binding of pVIc initiates contiguous conformational changes, analogous to falling dominos. There is a common pathway that branches into a pathway that leads to the repositioning of His-54 and another pathway that leads to the repositioning of Tyr-84.