9FCE

BelI in complex with SAM from Streptomyces sp. UCK14

Summary for 9FCE

• Entry DOI: 10.2210/pdb9fce/pdb
• Descriptor: SAM dependent methyltransferase, S-ADENOSYLMETHIONINE, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: natural product biosynthesis, enzyme mechanism, metal ion interaction, molecular docking, structure function relationships, transferase
• Biological source: Streptomyces sp.
• Total number of polymer chains: 2
• Total formula weight: 51752.42

Authors

Kuttenlochner, W.,Beller, P.,Kaysser, L.,Groll, M. (deposition date: 2024-05-15, release date: 2024-08-21, Last modification date: 2024-09-18)

Primary citation

Kuttenlochner, W.,Beller, P.,Kaysser, L.,Groll, M.
Deciphering the SAM- and metal-dependent mechanism of O-methyltransferases in cystargolide and belactosin biosynthesis: A structure-activity relationship study.
J.Biol.Chem., 300:107646-107646, 2024

PubMed Abstract: Cystargolides and belactosins are natural products with a distinct dipeptide structure and an electrophilic β-lactone warhead. They are known to inhibit proteases such as the proteasome or caseinolytic protease P, highlighting their potential in treating cancers and neurodegenerative diseases. Recent genetic analyses have shown homology between the biosynthetic pathways of the two inhibitors. Here, we characterize the O-methyltransferases BelI and CysG, which catalyze the initial step of β-lactone formation. Employing techniques such as crystallography, computational analysis, mutagenesis, and activity assays, we identified a His-His-Asp (HHD) motif in the active sites of the two enzymes, which is crucial for binding a catalytically active calcium ion. Our findings thus elucidate a conserved divalent metal-dependent mechanism in both biosynthetic pathways that distinguish BelI and CysG from previously characterized O-methyltransferases.

PubMed: 39121999
DOI: 10.1016/j.jbc.2024.107646

Experimental method

X-RAY DIFFRACTION (1.95 Å)