Some of the most challenging questions in biology involve understanding the structure and mechanism of action of the molecular machines that carry out the processes of life.

Structure determination of protein and protein nucleic acid complexes

These include:

• complexes that regulate post-translational modifications of chromatin (Schwabe, Panne and Schalch);
• complexes that determine the selection of alternative pre-mRNA splicing (Dominguez and Eperon);
• complexes that carry out DNA-repair (Chaplin);
• drug targets in complex with therapeutic antibodies (Carr);
• complexes that assemble to bring about apoptosis (Fox and Schwabe);
• complexes involved in respiratory disease (Gooptu and O'Hare);
• heme peroxidase enzyme complexes (Kwon and Moody);
• complexes involved in complement activation (Wallis) and,
• membrane ion channels (Vuister and Schmid).

Structural biology provides us enormous insight into the mechanism of action of macromolecules and complexes. At the same time it provides detailed insights into strategies to develop small and medium-sized molecules that can alter protein functions and serve as effective therapeutics.

Leicester has traditionally had considerable strength in utilising structural biology to enhance the drug discovery process. This is reflected by a long-term partnership with UCB and LifeArc (formerly MRC-Technology) which has led to considerable Impact in previous REF exercises (Carr).

More recently the engagement with drug discovery has been expanded to include a number of other researchers. This has resulted in:

• a successful GSK DPAc award to develop molecules to target the BCL6 transcriptional repression complex (Schwabe);
• an award from ELF to generate novel molecules to modulate alternative splicing (Dominguez and Eperon);
• molecular glues to enhance protective protein-protein interactions (Doveston);
• developing PROTACS to target large gene regulatory complexes (Hodgkinson) and,
• metallopharmaceuticals (Suntharalingam).

Many fundamental cellular processes rely on highly dynamic interactions between macromolecules and macromolecular complexes. Single molecule techniques allow us to observe and understand these processes in real time.

Using state-of-the-art single molecule microscopes developed within this Institute, we are investigating complex and dynamic biological processes including the initiation of transcription (Revyakin and Panne) and the assembly of splicing complexes (Eperon and Hudson).

These approaches allow us to address questions that are beyond the reach of other methods. This includes understanding the stoichiometry of protein assemblies and importantly, the nature of the dynamic processes through which large biological complexes are assembled. These approaches complement the static views provided by other structural biology approaches.

Understanding how macromolecules carry out their many diverse activities requires an understanding of the underlying chemistry which determines the behaviour of these complexes. By exploiting this chemistry, we are able to manipulate macromolecular function and activity. This is important both for drug development, as well as the development of research tools.

Creating a strong Chemical Biology group was a major part of the strategy when establishing the Institute. The goal was not only to leverage the power of chemistry to develop probes and tools to explore biological systems, but also to culture a ‘chemical view’ of the biology that would address questions that would otherwise be neglected.

For example, we are investigating the biological role of formaldehyde, a natural but neglected product of several important biological reactions in cells (Hopkinson). We are also asking whether chemical probes that stabilise proteins and protein:protein interactions may be an alternative approach to targeting biological systems (Doveston).

Taking a chemical approach to understanding biology has led to new insights into Heme as a regulator of ion channels and also to details of enzyme mechanisms (Ash, Hudson and Moody).