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Computer modelling of the NAD binding site of ADP‐ribosylating toxins: active‐site structure and mechanism of NAD binding
Author(s) -
Domenighini M.,
Montecucco C.,
Ripka W. C.,
Rappuoli R.
Publication year - 1991
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.1991.tb01822.x
Subject(s) - nad+ kinase , diphtheria toxin , adp ribosylation , binding site , biology , exotoxin , anthrax toxin , pseudomonas exotoxin , cholera toxin , biochemistry , homology modeling , active site , toxin , stereochemistry , mutagenesis , chemistry , microbiology and biotechnology , enzyme , recombinant dna , mutation , gene , fusion protein
Summary Summary Five ADP‐ribosylating bacterial toxins, pertussis toxin, cholera toxin, diphtheria toxin, Escherichia LT toxin and Pseudomonas exotoxin A, show significant homology in selected segments of their sequence. Site‐directed mutagenesis and chemical modification of residues within these regions cause loss of catalytic activity and of NAD binding. On the basis of these results and of molecular modelling based on the three‐dimensional structure of exotoxin A, the geometry of an NAD binding site common to all the toxins is deduced and described in the paper. For diphtheria toxin, sequence similarity with exotoxin A is such that its preliminary structure can be computed by molecular modelling, whereas for the other toxins similarity appears to be restricted to the NAD binding site. Moreover, an analysis of molecular fitting of the NAD molecule into its binding cavity suggests a new model for the conformation of the bound NAD that better accounts for all available experimental information.