Structural Insights into the CotB2-Catalyzed Cyclization of Geranylgeranyl Diphosphate to the Diterpene Cyclooctat-9-en-7-ol
2017
The
diterpenecyclase CotB2 catalyzes the cyclization of
geranylgeranyl diphosphate(GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique
carbon–carbon bondrearrangement combined with multiple hydride shifts, all occurring at a single active site. Here, we report the first high-resolution X-ray crystal structure of CotB2 with bound
substrate analog
geranylgeranylthiodiphosphate (GGSPP). In the GGSPP-bound form, GGSPP folds into a unique S-shaped conformation that probably reflects the substrate-bound state prior to ionization of the substrate GGPP. The folded framework of GGSPP is surrounded by hydrophobic residues and several aromatic and
asparagineresidues that are well-positioned to stabilize a series of reactive
carbocationintermediates through a combination of cation−π and dipole charge interactions. The combined crystal structures and mutagenesis-based biochemical assays provide a ...
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