Document Detail


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.
MedLine Citation:
PMID:  23043139     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Mary Lynn Baniecki; William J McGrath; Walter F Mangel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-07
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-03-26     Revised Date:  2014-01-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2081-91     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoviruses, Human / enzymology*,  genetics
Amino Acid Sequence
Capsid Proteins / chemistry*,  genetics,  metabolism
Crystallography, X-Ray
Cysteine Endopeptidases / chemistry*,  genetics,  metabolism
DNA, Viral / chemistry*,  metabolism
Enzyme Activation
Histidine / chemistry,  metabolism
Humans
Kinetics
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Precursors / chemistry*,  genetics,  metabolism
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Proteins / chemistry,  genetics,  metabolism
Thermodynamics
Tyrosine / chemistry,  metabolism
Grant Support
ID/Acronym/Agency:
AI R0141599/AI/NIAID NIH HHS; P41GM103473/GM/NIGMS NIH HHS; P41RR012408/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Capsid Proteins; 0/DNA, Viral; 0/Protein Precursors; 0/Recombinant Proteins; 0/polypeptide VI, adenovirus; 42HK56048U/Tyrosine; 4QD397987E/Histidine; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.39/adenain
Comments/Corrections

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