2H7X

Pikromycin Thioesterase adduct with reduced triketide affinity label

Summary for 2H7X

• Entry DOI: 10.2210/pdb2h7x/pdb
• Related: 1MNA 2H7Y
• Descriptor: Type I polyketide synthase PikAIV, SULFATE ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: thioesterase, alpha-beta hydrolase, hydrolase
• Biological source: Streptomyces venezuelae
• Total number of polymer chains: 2
• Total formula weight: 68468.73

Authors

Giraldes, J.W.,Akey, D.L.,Kittendorf, J.D.,Sherman, D.H.,Smith, J.S.,Fecik, R.A. (deposition date: 2006-06-05, release date: 2006-09-19, Last modification date: 2024-10-09)

Primary citation

Giraldes, J.W.,Akey, D.L.,Kittendorf, J.D.,Sherman, D.H.,Smith, J.S.,Fecik, R.A.
Structural and Mechanistic Insights of Polyketide Macrolactonization from Polyketide-based Affinity Labels
NAT.CHEM.BIOL., 2:531-536, 2006

PubMed Abstract: Polyketides are a diverse class of natural products having important clinical properties, including antibiotic, immunosuppressive and anticancer activities. They are biosynthesized by polyketide synthases (PKSs), which are modular, multienzyme complexes that sequentially condense simple carboxylic acid derivatives. The final reaction in many PKSs involves thioesterase-catalyzed cyclization of linear chain elongation intermediates. As the substrate in PKSs is presented by a tethered acyl carrier protein, introduction of substrate by diffusion is problematic, and no substrate-bound type I PKS domain structure has been reported so far. We describe the chemical synthesis of polyketide-based affinity labels that covalently modify the active site serine of excised pikromycin thioesterase from Streptomyces venezuelae. Crystal structures reported here of the affinity label-pikromycin thioesterase adducts provide important mechanistic insights. These results suggest that affinity labels can be valuable tools for understanding the mechanisms of individual steps within multifunctional PKSs and for directing rational engineering of PKS domains for combinatorial biosynthesis.

PubMed: 16969373
DOI: 10.1038/nchembio822

Experimental method

X-RAY DIFFRACTION (1.85 Å)