4EKF: Structure of the Inactive Adenovirus Proteinase at 0.98 Angstrom Resolution

Citation:
Abstract
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.
PDB ID: 4EKFDownload
MMDB ID: 103787
PDB Deposition Date: 2012/4/9
Updated in MMDB: 2012/12 
Experimental Method:
x-ray diffraction
Resolution: 0.98  Å
Source Organism:
Similar Structures:
Biological Unit for 4EKF: monomeric; determined by author and by software (PISA)
Molecular Components in 4EKF
Label Count Molecule
Protein (1 molecule)
1
Adenain
(Gene: L3)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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