4UIO

Structure of the Salmonella typhi Type I Dehydroquinase covalently inhibited by a 3-dehydroquinic acid derivative

4UIO の概要

• エントリーDOI: 10.2210/pdb4uio/pdb
• 分子名称: 3-DEHYDROQUINATE DEHYDRATASE, (1~{R},3~{R},4~{S},5~{R})-3-methyl-1,3,4,5-tetrakis(oxidanyl)cyclohexane-1-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: bacterial proteins, binding sites, crystallization, lyase, inhibitor, protein binding, shikimis acid pathway, substrate specificity
• 由来する生物種: SALMONELLA ENTERICA SUBSP. ENTERICA SEROVAR TYPHI
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28004.07

構造登録者

Otero, J.M.,Llamas-Saiz, A.L.,Tizon, L.,Lence, E.,Thompson, P.,Hawkins, A.R.,Gonzalez-Bello, C.,van Raaij, M.J. (登録日: 2015-03-30, 公開日: 2015-07-15, 最終更新日: 2024-11-06)

主引用文献

Gonzalez-Bello, C.,Tizon, L.,Lence, E.,Otero, J.M.,van Raaij, M.J.,Martinez-Guitian, M.,Beceiro, A.,Thompson, P.,Hawkins, A.R.
Chemical Modification of a Dehydratase Enzyme Involved in Bacterial Virulence by an Ammonium Derivative: Evidence of its Active Site Covalent Adduct.
J.Am.Chem.Soc., 137:9333-9343, 2015

PubMed Abstract: The first example of an ammonium derivative that causes a specific modification of the active site of type I dehydroquinase (DHQ1), a dehydratase enzyme that is a promising target for antivirulence drug discovery, is described. The resolution at 1.35 Å of the crystal structure of DHQ1 from Salmonella typhi chemically modified by this ammonium derivative revealed that the ligand is covalently attached to the essential Lys170 through the formation of an amine. The detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism and the experimentally observed differences between S. typhi and Staphylococcus aureus enzymes. The results presented here reveal that the replacement of Phe225 in St-DHQ1 by Tyr214 in Sa-DHQ1 and its hydrogen bonding interaction with the conserved water molecule observed in several crystal structures protects the amino adduct against further dehydration/aromatization reactions. In contrast, for the St-DHQ1 enzyme, the carboxylate group of Asp114, with the assistance of this water molecule, would trigger the formation of a Schiff base that can undergo further dehydration reactions until full aromatization of the cyclohexane ring is achieved. Moreover, in vitro antivirulence studies showed that the reported compound is able to reduce the ability of Salmonella Enteritidis to kill A459 respiratory cells. These studies have identified a good scaffold for the design of irreversible inhibitors that can be used as drugs and has opened up new opportunities for the development of novel antivirulence agents by targeting the DHQ1 enzyme.

PubMed: 26148116
DOI: 10.1021/JACS.5B04080

実験手法

X-RAY DIFFRACTION (1.35 Å)