title: 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.
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 Å 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 α + β fold; the major structural differences between them lie in the β-sheet domain. In AVP-pVIc, the general base His-54 Nδ1 is 3.9 Å away from the Cys-122 Sγ, thereby rendering it nucleophilic. In AVP, however, His-54 Nδ1 is 7.0 Å away from Cys-122 Sγ, too far away to be able to abstract the proton from Cys-122. In AVP-pVIc, Tyr-84 forms a cation-π 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 Å 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.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Baniecki
authors.forename: William J
authors.initials: WJ
authors.lastname: McGrath
authors.forename: Walter F
authors.initials: WF
authors.lastname: Mangel
mesh_terms: D000260:Adenoviruses, Human / Q000201:enzymology* / Q000235:genetics; D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; D004279:DNA, Viral; D011498:Protein Precursors; D011994:Recombinant Proteins; C090876:polypeptide VI, adenovirus; D014443:Tyrosine; D006639:Histidine; D003546:Cysteine Endopeptidases; C091827:adenain