Structural Biology

Bioinformatics methods for structural biology are complex yet are relatively under-developed compared with other methods. The biological function of a protein is largely determined by its three-dimensional (3D) structure. Understanding the 3D structure taken up by a microbial protein could potentially allow us to investigate the effect of amino acid sequence changes in, for example:

• Antimicrobial susceptibility and resistance
• Microbial antigenicity
• The ability of a microorganism to infect, colonise (or persist in) a particular host species.

Further to this, the ability to reliably predict protein structures should allow us to investigate protein 'docking' i.e. study of the interaction between proteins at the molecular level.

This could lead to greatly improved understanding of, for example, viral morphogenesis, which would be an important step in the development of antimicrobial strategies.

These structural biology methods, potentially, have great benefit for the HPA, particularly in tandem with other activities relating to SNP detection and characterization. However application of these techniques can be limited by the need for certain initial structural data and the requirement to validate predictions in vitro. Given these restrictions, and the inherently time-consuming nature of the process, projects are carefully selected by critical review.

The first structural project to be undertaken was to investigate the preferential binding of Norwalk virus to specific human blood group histo-antigens of the ABO(h) system. The structure of Norwalk virus (left) is publicly available, and the ABO antigen structures can be created from existing carbohydrate models. Models of the virus-antigen interaction did not support published in vitro results, although previously unreported regions of preferential interaction were discovered.

A second project investigated the structural basis for resistance to quinolones and fluoroquinolones in DNA gyrase (right). (Fluoro)quinolones are powerful antimicrobial agents, however resistance is being developed in many organisms of public health significance. The target of these drugs is DNA gyrase, an enzyme responsible for DNA coiling, and it is hypothesised that single amino acid substitutions induce resistance through structural alterations. Docking studies showed that the drug (red) binds between DNA (purple) and gyrase (blue/white) preventing DNA interaction with catalytic residues. Mutations in certain gyrase residues (blue) block this binding site, providing resistance. In silico results corroborated published laboratory findings.

We are currently seeking further projects and welcome collaboration with partners from across the Agency and its collaborating organisations. Please contact us if you would like to discuss this further.

Last reviewed: 18 August 2008