Crystal Structure of Cockroach Allergen Bla g 2, an Unusual Zinc Binding Aspartic Protease with a Novel Mode of Self-inhibition

The crystal structure of Bla g 2 was solved in order to investigate the structural basis for the allergenic properties of this unusual protein. This is the first structure of an aspartic protease in which conserved glycine residues, in two canonical DTG triads, are substituted by different amino aci...

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Bibliographic Details
Published in:Journal of molecular biology 2005-04, Vol.348 (2), p.433-444
Main Authors: Gustchina, Alla, Li, Mi, Wünschmann, Sabina, Chapman, Martin D., Pomés, Anna, Wlodawer, Alexander
Format: Article
Language:English
Subjects:
active site
allergy
Amino Acid Sequence
AMINO ACIDS
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - chemistry
Aspartic Acid Endopeptidases - metabolism
aspartic proteases
Binding Sites
Cockroaches - enzymology
CRYSTAL STRUCTURE
Crystallography, X-Ray
DISULFIDES
GLYCINE
Humans
MATERIALS SCIENCE
metal binding
Models, Molecular
Molecular Sequence Data
PHENYLALANINE
Protein Folding
Protein Structure, Tertiary
RESIDUES
self-inhibition
Sequence Alignment
STABILITY
Structural Homology, Protein
ZINC
Zinc - metabolism
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Summary:The crystal structure of Bla g 2 was solved in order to investigate the structural basis for the allergenic properties of this unusual protein. This is the first structure of an aspartic protease in which conserved glycine residues, in two canonical DTG triads, are substituted by different amino acid residues. Another unprecedented feature revealed by the structure is the single phenylalanine residue insertion on the tip of the flap, with the side-chain occupying the S1 binding pocket. This and other important amino acid substitutions in the active site region of Bla g 2 modify the interactions in the vicinity of the catalytic aspartate residues, increasing the distance between them to ∼4 Å and establishing unique direct contacts between the flap and the catalytic residues. We attribute the absence of substantial catalytic activity in Bla g 2 to these unusual features of the active site. Five disulfide bridges and a Zn-binding site confer stability to the protein, which may contribute to sensitization at lower levels of exposure than other allergens.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2005.02.062