7AO0

Crystal structure of CotB2 variant F107A in complex with alendronate

Summary for 7AO0

• Entry DOI: 10.2210/pdb7ao0/pdb
• Related: 4OMG 4OMH 6GGI 6GGJ 6GGK 6GGL
• Descriptor: Cyclooctat-9-en-7-ol synthase, 4-AMINO-1-HYDROXYBUTANE-1,1-DIYLDIPHOSPHONATE, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (6 entities in total)
• Functional Keywords: terpene synthase, cyclooctatin, lyase
• Biological source: Streptomyces melanosporofaciens
• Total number of polymer chains: 2
• Total formula weight: 74568.41

Authors

Dimos, N.,Driller, R.,Loll, B. (deposition date: 2020-10-13, release date: 2020-12-02, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.93 Å)