Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 404, Issue 5, Pages 890-901Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.10.019
Keywords
docking; enzyme inhibition; glutamate kinase; pyrroline-5-carboxylate; synthase; proline
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Funding
- Spanish Ministerio de Ciencia e Innovacion [BFU2007-66781]
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Proline, the feedback inhibitor of bacterial glutamate kinase (GK) and plant pyrroline-5-carboxylate synthase (P5CS) enzymes, is a key regulator of the osmotic and redox balance of cells Using kinetic assays, site-directed mutagenesis, structure activity analyses, and docking calculations, we have identified the binding site of this metabolite in three-dimensional structures of Escherichia cob and Campylobacter jejuni GKs The proline-binding cavity partially overlaps with the glutamate substrate site, and the interaction of both proline and glutamate with GK is modulated by a flexible, 16-residue loop linking beta-sheet 4 and alpha-helix E in the active-center cavity This loop is also critical for regulation of plant and human P5CSs Furthermore, our results indicate that the functional unit of the E colt enzyme is dimeric and contains an intermolecular hydrogen-bond network that interconnects the active-center cavities of the monomers and is important for substrate binding (C) 2010 Elsevier Ltd All rights reserved
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