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Dimerisation induced formation of the active site and the identification of three metal sites in EAL-phosphodiesterases

DOI: 10.1038/srep42166 DOI Help

Authors: Dom Bellini (Diamond Light Source) , Sam Horrell (Diamond Light Source; University of Essex) , Andrew Hutchin (Diamond Light Source; University of Southampton) , Curtis Phippen (The University of Southampton) , Richard W. Strange (University of Essex) , Yuming Cai (The University of Southampton) , Armin Wagner (Diamond Light Source) , Jeremy S. Webb (The University of Southampton) , Ivo Tews (The University of Southampton) , Martin A. Walsh (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 7

State: Published (Approved)
Published: February 2017
Diamond Proposal Number(s): 11175 , 8663 , 8889

Open Access Open Access

Abstract: The bacterial second messenger cyclic di-3′,5′-guanosine monophosphate (c-di-GMP) is a key regulator of bacterial motility and virulence. As high levels of c-di-GMP are associated with the biofilm lifestyle, c-di-GMP hydrolysing phosphodiesterases (PDEs) have been identified as key targets to aid development of novel strategies to treat chronic infection by exploiting biofilm dispersal. We have studied the EAL signature motif-containing phosphodiesterase domains from the Pseudomonas aeruginosa proteins PA3825 (PA3825EAL) and PA1727 (MucREAL). Different dimerisation interfaces allow us to identify interface independent principles of enzyme regulation. Unlike previously characterised two-metal binding EAL-phosphodiesterases, PA3825EAL in complex with pGpG provides a model for a third metal site. The third metal is positioned to stabilise the negative charge of the 5′-phosphate, and thus three metals could be required for catalysis in analogy to other nucleases. This newly uncovered variation in metal coordination may provide a further level of bacterial PDE regulation.

Journal Keywords: Bacterial pathogenesis; X-ray crystallography

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 13/02/2017 11:58


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)