Crystallographic structure at 1.6-Å resolution of the human adenovirus proteinase in a covalent complex with its 11-amino-acid peptide cofactor: Insights on a new fold

William J. McGrath, Jianzhong Ding, Aashish Didwania, Robert M. Sweet, Walter F. Mangel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The crystal structure of the human adenovirus proteinase (AVP), a cysteine proteinase covalently bound to its 11-amino-acid peptide cofactor pVIc, has been solved to 1.6-Å resolution with a crystallographic R-factor of 0.136, Rfree=0.179. The fold of AVP-pVIc is new and the structural basis for it is described in detail. The polypeptide chain of AVP folds into two domains. One domain contains a five-strand β-sheet with two peripheral α-helices; this region represents the hydrophobic core of the protein. A second domain contains the N terminus, several C-terminal α-helices, and a small peripheral anti-parallel β-sheet. The domains interact through an extended polar interface. pVIc spans the two domains like a strap, its C-terminal portion forming a sixth strand on the β-sheet. The active site is in a long, deep groove located between the two domains. Portions are structurally similar to the active site of the prototypical cysteine proteinase papain, especially some of the Cα backbone atoms (r.m.s. deviation of 0.354 Å for 12 Cα atoms). The active-site nucleophile of AVP, the conserved Cys122, was shown to have a pKa of 4.5, close to the pKa of 3.0 for the nucleophile of papain, suggesting that a similar ion pair arrangement with His54 may be present in AVP-pVIc. The interactions between AVP and pVIc include 24 non-β-strand hydrogen bonds, six β-strand hydrogen bonds and one covalent bond. Of the 204 amino acid residues in AVP, 33 are conserved among the many serotypes of adenovirus, and these aid in forming the active site groove, are involved in substrate specificity or interact between secondary structure elements.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1648
Issue number1-2
DOIs
StatePublished - May 30 2003
Externally publishedYes

Keywords

  • Active-site nucleophile
  • Cysteine proteinase
  • Peptide cofactor
  • Viral proteinase
  • X-ray crystallographic refinement

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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