There is a rapid increase in human infections resistant to multiple antibiotics, and researchers are working hard to find ways to stem this superbug tide. Chemists in the Redinbo Group have now revealed the structure of an enzyme that helps antibiotic resistance genes to hop to new bacterial hosts - one route to superbug status. The team, published in PNAS, also describe molecules that block the enzyme's activity. Though the molecules are far from benign drugs, the authors say the strategy represents a new idea for fighting superbugs.
To pass on antibiotic-thwarting genes to a nearby microorganism, a bacterium needs an enzyme to cut one strand of its own DNA. The Redinbo Group crystallized a complex of DNA and this nicking enzyme, which they obtained from a dangerous strain of methicillin-resistant Staphylococcus aureus - MRSA - the first human pathogen to also pick up resistance to antibiotic heavy hitter vancomycin. They noticed two protein loops holding the DNA, "pinching it like a finger and a thumb," says Redinbo, arranging it for nicking. The nicked DNA strand peels off, so the bacterium can squirt it into its neighbors. Eliminating those loops from the enzyme makes Staphylococcus far less able to share DNA. The long-term goal of this work is to develop a companion therapy to traditional antibiotics that keeps resistance in check.
Protein arginine methyltransferase 10 (PRMT10) is a type I arginine methyltransferase that is essential for regulating flowering time in Arabidopsis thaliana. Scientists in the Redinbo Group present in the Journal of Molecular Biology, a 2.6 Å resolution crystal structure of A. thaliana PRMT 10 (AtPRMT10) in complex with a reaction product, S-adenosylhomocysteine. The structure reveals a dimerization arm that is 12–20 residues longer than PRMT structures elucidated previously; as a result, the essential AtPRMT10 dimer exhibits a large central cavity and a distinctly accessible active site.
The researchers employed molecular dynamics to examine how dimerization facilitates AtPRMT10 motions necessary for activity, and they show that these motions are conserved in other PRMT enzymes. Finally, functional data reveal that the 10 N-terminal residues of AtPRMT10 influence substrate specificity, and that enzyme activity is dependent on substrate protein sequences distal from the methylation site. Taken together, these data provide insights into the molecular mechanism of AtPRMT10, as well as other members of the PRMT family of enzymes. They highlight differences between AtPRMT10 and other PRMTs but also indicate that motions are a conserved element of PRMT function.