5DM4

Crystal structure of the plantazolicin methyltransferase BpumL in complex with pentazolic desmethylPZN analog and SAH

Summary for 5DM4

• Entry DOI: 10.2210/pdb5dm4/pdb
• Related: 5DLY 5DM1 5DM2
• Descriptor: Methyltransferase domain family, S-ADENOSYL-L-HOMOCYSTEINE, GLYCEROL, ... (5 entities in total)
• Functional Keywords: n-methyltransferase, plantazolicin, pentazolic desmethylpzn analog, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Bacillus pumilus ATCC 7061
• Total number of polymer chains: 1
• Total formula weight: 31415.75

Authors

Hao, Y.,Nair, S.K. (deposition date: 2015-09-07, release date: 2015-09-23, Last modification date: 2024-03-13)

Primary citation

Hao, Y.,Blair, P.M.,Sharma, A.,Mitchell, D.A.,Nair, S.K.
Insights into methyltransferase specificity and bioactivity of derivatives of the antibiotic plantazolicin.
Acs Chem.Biol., 10:1209-1216, 2015

PubMed Abstract: Peptide antibiotics represent a class of conformationally constrained natural products of growing pharmaceutical interest. Plantazolicin (PZN) is a linear, polyheterocyclic natural product with highly selective and potent activity against the anthrax-causing bacterium, Bacillus anthracis. The bioactivity of PZN is contingent on dimethylation of its N-terminal Arg residue by an S-adenosylmethionine-dependent methyltransferase. Here, we explore the substrate tolerances of two homologous PZN methyltransferases by carrying out kinetic analyses of the enzymes against a synthetic panel of truncated PZN analogs containing the N-terminal Arg residue. X-ray cocrystal structures of the PZN methyltransferases with each of these heterocycle-containing substrates provide a rationale for understanding the strict substrate specificity of these enzymes. Kinetic studies of structure-guided, site-specific variants allowed for the assignment of residues governing catalysis and substrate scope. Microbiological testing further revealed that upon dimethylation of the N-terminal Arg, a pentaheterocyclized PZN analog retained potent anti-B. anthracis activity, nearly equal to that of full-length PZN. These studies may be useful in the biosynthetic engineering of natural product analogs with different bioactivity profiles, as demonstrated by our identification of a truncated plantazolicin derivative that is active against methicillin-resistant Staphylococcus aureus (MRSA).

PubMed: 25635336
DOI: 10.1021/cb501042a

Experimental method

X-RAY DIFFRACTION (1.75 Å)