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On the basis of the structure of a HslUV complex, a mechanism of allosteric activation of the HslV protease, wherein binding of the HslU chaperone propagates a conformational change to the active site cleft of the protease, has been proposed. Here, the 3.1 A X-ray crystallographic structure of Haemophilus influenzae HslUV complexed with a vinyl sulfone inhibitor is described. The inhibitor, which reacts to form a covalent linkage to Thr1 of HslV, binds in an "antiparallel beta" manner, with hydrogen-bond interactions between the peptide backbone of the protease and that of the inhibitor, and with two leucinyl side chains of the inhibitor binding in the S1 and S3 specificity pockets of the protease. Comparison of the structure of the HslUV-inhibitor complex with that of HslV without inhibitor and in the absence of HslU reveals that backbone interactions would correctly position a substrate for cleavage in the HslUV complex, but not in the HslV protease alone, corroborating the proposed mechanism of allosteric activation. This activation mechanism differs from that of the eukaryotic proteasome, for which binding of activators opens a gated channel that controls access of substrates to the protease, but does not perturb the active site environment.

Original publication




Journal article


J Mol Biol

Publication Date





779 - 785


ATP-Dependent Proteases, Adenosine Triphosphatases, Allosteric Regulation, Catalytic Domain, Crystallography, X-Ray, Cysteine Endopeptidases, Endopeptidases, Enzyme Activation, Haemophilus influenzae, Heat-Shock Proteins, Macromolecular Substances, Models, Molecular, Multienzyme Complexes, Protease Inhibitors, Proteasome Endopeptidase Complex, Protein Conformation, Recombinant Proteins, Serine Endopeptidases, Substrate Specificity, Sulfones