Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Conformational change and ligand binding in the aristolochene synthase catalytic cycle

van der Kamp, Marc W., Sirirak, Jitnapa, Zurek, Jolanta, Allemann, Rudolf Konrad and Mulholland, Adrian J. 2013. Conformational change and ligand binding in the aristolochene synthase catalytic cycle. Biochemistry 52 (45) , pp. 8094-8105. 10.1021/bi400898k

Full text not available from this repository.

Abstract

Terpene synthases are potentially useful biocatalysts for the synthesis of valuable compounds, such as anticancer drugs and antibiotics. The design of altered activities requires better knowledge of their mechanisms, for example, an understanding of the complex conformational changes that are part of their catalytic cycle, how they are coordinated, and what drives them. Crystallographic studies of the sesquiterpene synthase artistolochene synthase have led to a proposed sequence of ligand binding and conformational change but have provided only indirect insight. Here, we have performed extensive molecular dynamics simulations of multiple enzyme–ligand complexes (over 2 μs in total). The simulations provide clear evidence of what drives the conformational changes required for reaction. They support a picture in which the substrate farnesyl diphosphate binds first, followed by three magnesium ions in sequence, and, after reaction, the release of aristolochene and two magnesium ions followed by the final magnesium ion and diphosphate. Binding of farnesyl diphosphate leads to an increased level of sampling of open conformations, allowing the first two magnesium ions to bind. The closed enzyme conformation is maintained with a diphosphate moiety and two magnesium ions bound. The open-to-closed transition reduces flexibility around the active site entrance, partly through a lid closing over it. The simulations with all three magnesium ions and farnesyl diphosphate bound provide, for the first time, a realistic model of the Michaelis complex involved in reaction, which is inaccessible to experimental structural studies. These insights could help with the design of altered activities in a range of terpene synthases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
ISSN: 0006-2960
Last Modified: 04 Jun 2017 06:33
URI: http://orca.cf.ac.uk/id/eprint/61970

Citation Data

Cited 2 times in Google Scholar. View in Google Scholar

Cited 24 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item