Article Metrics


Online attention

(p)ppGpp regulates a bacterial nucleosidase by an allosteric two-domain switch

DOI: 10.1016/j.molcel.2019.03.035 DOI Help

Authors: Yong Everett Zhang (University of Copenhagen) , René Lysdal Bærentsen (Aarhus University) , Tobias Fuhrer (ETH Zurich) , Uwe Sauer (ETH Zurich) , Kenn Gerdes (University of Copenhagen) , Ditlev Egeskov Brodersen (Aarhus University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 17844

Abstract: The stringent response alarmones pppGpp and ppGpp are essential for rapid adaption of bacterial physiology to changes in the environment. In Escherichia coli, the nucleosidase PpnN (YgdH) regulates purine homeostasis by cleaving nucleoside monophosphates and specifically binds (p)ppGpp. Here, we show that (p)ppGpp stimulates the catalytic activity of PpnN both in vitro and in vivo causing accumulation of several types of nucleobases during stress. The structure of PpnN reveals a tetramer with allosteric (p)ppGpp binding sites located between subunits. pppGpp binding triggers a large conformational change that shifts the two terminal domains to expose the active site, providing a structural rationale for the stimulatory effect. We find that PpnN increases fitness and adjusts cellular tolerance to antibiotics and propose a model in which nucleotide levels can rapidly be adjusted during stress by simultaneous inhibition of biosynthesis and stimulation of degradation, thus achieving a balanced physiological response to constantly changing environments.

Journal Keywords: YgdH; PpnN; allosteric enzyme; nucleotide metabolism; stringent response; antibiotic tolerance; persistence; fluoroquinolone

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 24/04/2019 09:32

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)