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X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis

Shishova, Ekaterina Y., Yu, Fanglei, Miller, David James, Faraldos, Juan A., Zhao, Yuxin X., Coates, Robert M., Allemann, Rudolf Konrad, Cane, David E. and Christianson, David W. 2008. X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis. Journal of Biological Chemistry 283 (22) , pp. 15431-15439. 10.1074/jbc.M800659200

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Abstract

The universal sesquiterpene precursor, farnesyl diphosphate (FPP), is cyclized in an Mg2+-dependent reaction catalyzed by the tetrameric aristolochene synthase from Aspergillus terreus to form the bicyclic hydrocarbon aristolochene and a pyrophosphate anion (PPi) coproduct. The 2.1-Å resolution crystal structure determined from crystals soaked with FPP reveals the binding of intact FPP to monomers A-C, and the binding of PPi and Mg2+B to monomer D. The 1.89-Å resolution structure of the complex with 2-fluorofarnesyl diphosphate (2F-FPP) reveals 2F-FPP binding to all subunits of the tetramer, with Mg2+Baccompanying the binding of this analogue only in monomer D. All monomers adopt open activesite conformations in these complexes, but slight structural changes in monomers C and D of each complex reflect the very initial stages of a conformational transition to the closed state. Finally, the 2.4-Å resolution structure of the complex with 12,13-difluorofarnesyl diphosphate (DF-FPP) reveals the binding of intact DF-FPP to monomers A-C in the open conformation and the binding of PPi, Mg2+B, and Mg2+C to monomer D in a predominantly closed conformation. Taken together, these structures provide 12 independent “snapshots” of substrate or product complexes that suggest a possible sequence for metal ion binding and conformational changes required for catalysis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Cardiff Catalysis Institute (CCI)
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: EPSRC
Last Modified: 04 Jun 2017 01:56
URI: http://orca.cf.ac.uk/id/eprint/6121

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