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The structure of PghL hydrolase bound to its substrate poly-γ-glutamate

DOI: 10.1111/febs.14688 DOI Help

Authors: Sneha Ramaswamy (King's College London) , Masooma Rasheed (King's College London) , Carlo F. Morelli (University of Milano) , Cinzia Calvio (University of Pavia) , Brian J. Sutton (King's College London) , Annalisa Pastore (King's College London; University of Pavia)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Febs Journal

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 9495

Open Access Open Access

Abstract: The identification of new strategies to fight bacterial infections in view of the spread of multiple resistance to antibiotics has become mandatory. It has been demonstrated that several bacteria develop poly‐γ‐glutamic acid (γ‐PGA) capsules as a protection from external insults and/or host defence systems. Among the pathogens that shield themselves in these capsules are B. anthracis, F. tularensis and several Staphylococcus strains. These are important pathogens with a profound influence on human health. The recently characterised γ‐PGA hydrolases, which can dismantle the γ‐PGA‐capsules, are an attractive new direction that can offer real hope for the development of alternatives to antibiotics, particularly in cases of multidrug resistant bacteria. We have characterised in detail the cleaving mechanism and stereospecificity of the enzyme PghL (previously named YndL) from B. subtilis encoded by a gene of phagic origin and dramatically efficient in degrading the long polymeric chains of γ‐PGA. We used X‐ray crystallography to solve the three‐dimensional structures of the enzyme in its zinc‐free, zinc‐bound and complexed forms. The protein crystallised with a γ‐PGA hexapeptide substrate and thus reveals details of the interaction which could explain the stereospecificity observed and give hints on the catalytic mechanism of this class of hydrolytic enzymes.

Journal Keywords: Poly‐γ‐glutamate; capsule; PGA‐hydrolase; virulence; Staphylococci; biofilm inhibitor; anti‐microbial drug

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 12/11/2018 09:17

Documents:
febs.14688.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags: