Solving this structure meant that the researchers could at last determine just how DksA helped ppGpp hold fast to its target, RNA polymerase.

DksA uses something scientists call the "backdoor of gene expression," a cavity on the RNA polymerase molecule called the secondary channel. DksA squeezes through this narrow tunnel toward the site where ppGpp binds to the enzyme. Once here, the protein helps ppGpp stay bound to RNA polymerase.

"The secondary channel seems to be the hotspot for many interactions," Artsimovitch said. "It leads straight to the active site, and presents a confined area where many proteins and antibiotics that control transcription may bind to carry out their business."

Knowing what roles ppGpp and DksA play in how bacteria respond to stress and other physiological stimuli may help scientists create new antibacterial drugs that target mechanisms specific and unique to harmful bacteria.

"Conventional antibiotics aimed at killing bacteria also put immense pressure on bacteria to survive, and to ultimately develop resistance to these drugs," Artsimovitch said. "Forcing harmful bacteria into a stationary state by controlling ppGpp levels may be the way to circumvent the rise in antibiotic resistance.

"ppGpp and DksA are found in all bacteria, including harmful ones," she continued. "Using ppGpp-based compounds to shut down gene expression in harmful bacteria could help curb the spread of infections."

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Contact: Irina Artsimovitch
artsimovitch.1@osu.edu
614-292-6777
Ohio State University
5-Aug-2004