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Lookup NU author(s): Dr Heather Lamb, Professor Alastair Hawkins
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The binding mode of several substrate analogues, (2R)-2-benzyl-3- dehydroquinic acids 4, which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p-methoxybenzyl derivative 4a, have been solved at 2.40 Å and 2.75 Å, respectively. This has allowed the resolution of the M. tuberculosis DHQ2 loop containing residues 20-25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4b-d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
Author(s): Peón A, Otero J, Tizón L, Prazeres V, Llamas-Saiz A, Fox G, Van Raaij M, Lamb H, Hawkins A, Gago F, Castedo L, González-Bello C
Publication type: Article
Publication status: Published
Journal: ChemMedChem
Year: 2010
Volume: 5
Issue: 10
Pages: 1726-1733
Print publication date: 02/09/2010
ISSN (print): 1860-7179
ISSN (electronic): 1860-7187
Publisher: Wiley - VCH Verlag GmbH & Co. KGaA
URL: http://dx.doi.org/10.1002/cmdc.201000281
DOI: 10.1002/cmdc.201000281
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