7AO2

Crystal structure of CotB2 variant W288G in complex with alendronate

7AO2 の概要

• エントリーDOI: 10.2210/pdb7ao2/pdb
• 関連するPDBエントリー: 4OMG 4OMH 6GGI 6GGJ 6GGK 6GGL
• 分子名称: Cyclooctat-9-en-7-ol synthase, (4S)-2-METHYL-2,4-PENTANEDIOL, 4-AMINO-1-HYDROXYBUTANE-1,1-DIYLDIPHOSPHONATE, ... (6 entities in total)
• 機能のキーワード: terpene synthase, cyclooctatin, lyase
• 由来する生物種: Streptomyces melanosporofaciens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 74225.94

構造登録者

Dimos, N.,Driller, R.,Loll, B. (登録日: 2020-10-13, 公開日: 2020-12-02, 最終更新日: 2024-01-31)

主引用文献

Raz, K.,Driller, R.,Dimos, N.,Ringel, M.,Bruck, T.,Loll, B.,Major, D.T.
The Impression of a Nonexisting Catalytic Effect: The Role of CotB2 in Guiding the Complex Biosynthesis of Cyclooctat-9-en-7-ol.
J.Am.Chem.Soc., 142:21562-21574, 2020

PubMed Abstract: Terpene synthases generate terpenes employing diversified carbocation chemistry, including highly specific ring formations, proton and hydride transfers, and methyl as well as methylene migrations, followed by reaction quenching. In this enzyme family, the main catalytic challenge is not rate enhancement, but rather structural and reactive control of intrinsically unstable carbocations in order to guide the resulting product distribution. Here we employ multiscale modeling within classical and quantum dynamics frameworks to investigate the reaction mechanism in the diterpene synthase CotB2, commencing with the substrate geranyl geranyl diphosphate and terminating with the carbocation precursor to the final product cyclooctat-9-en-7-ol. The 11-step in-enzyme carbocation cascade is compared with the same reaction in the absence of the enzyme. Remarkably, the free energy profiles in gas phase and in CotB2 are surprisingly similar. This similarity contrasts the multitude of strong π-cation, dipole-cation, and ion-pair interactions between all intermediates in the reaction cascade and the enzyme, suggesting a remarkable balance of interactions in CotB2. We ascribe this balance to the similar magnitude of the interactions between the carbocations along the reaction coordinate and the enzyme environment. The effect of CotB2 mutations is studied using multiscale mechanistic docking, machine learning, and X-ray crystallography, pointing the way for future terpene synthase design.

PubMed: 33289561
DOI: 10.1021/jacs.0c11348

実験手法

X-RAY DIFFRACTION (1.75 Å)