6WP9

AvaR1 bound to Avenolide

Summary for 6WP9

• Entry DOI: 10.2210/pdb6wp9/pdb
• Related: 6WP7
• Descriptor: AvaR1, (5S)-5-[(6R)-6-hydroxy-6-methyl-5-oxooctyl]furan-2(5H)-one (3 entities in total)
• Functional Keywords: transcriptional repressor bound ligand, dna binding protein, dna binding protein-inhibitor complex, dna binding protein-hormone complex, dna binding protein/hormone
• Biological source: Streptomyces avermitilis
• Total number of polymer chains: 8
• Total formula weight: 217839.08

Authors

Kapoor, I.,Olivares, P.J.,Nair, S.K. (deposition date: 2020-04-26, release date: 2020-07-22, Last modification date: 2023-10-18)

Primary citation

Kapoor, I.,Olivares, P.,Nair, S.K.
Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones.
Elife, 9:-, 2020

PubMed Abstract: Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates the production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic diseases. Butenolides and γ-butyrolactones control the production of pharmaceutically important secondary metabolites by binding to TetR family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy for the production of avenolide. We present crystal structures of the butenolide receptor AvaR1 in isolation and in complex with avenolide, as well as those of AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable the identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding the regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines.

PubMed: 32510324
DOI: 10.7554/eLife.57824

Experimental method

X-RAY DIFFRACTION (2 Å)