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| Home > Publications database > Substrate Locking Promotes Dimer-Dimer Docking of an Enzyme Antibiotic Target |
| Home > Publications database > Substrate Locking Promotes Dimer-Dimer Docking of an Enzyme Antibiotic Target |
| Journal Article | FZJ-2018-07248 |
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2018
Cell Press
Cambridge, Mass.
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Please use a persistent id in citations: doi:10.1016/j.str.2018.04.014
Abstract: Protein dynamics manifested through structural flex-ibility play a central role in the function of biologicalmolecules. Here we explore the substrate-mediatedchange in protein flexibility of an antibiotic targetenzyme, Clostridium botulinum dihydrodipicolinatesynthase. We demonstrate that the substrate, pyru-vate, stabilizes the more active dimer-of-dimers ortetrameric form. Surprisingly, there is little differencebetween the crystal structures of apo and substrate-bound enzyme, suggesting protein dynamics may beimportant. Neutron and small-angle X-ray scatteringexperiments were used to probe substrate-induceddynamics on the sub-second timescale, but nosignificant changes were observed. We thereforedeveloped a simple technique, coined protein dy-namics-mass spectrometry (ProD-MS), which en-ables measurement of time-dependent alkylation ofcysteine residues. ProD-MS together with X-raycrystallography and analytical ultracentrifugationanalyses indicates that pyruvate locks the conforma-tion of the dimer that promotes docking to the moreactive tetrameric form, offering insight into ligand-mediated stabilization of multimeric enzymes.
Keyword(s): Health and Life (1st) ; Biology (2nd)
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