Overview
The context of our research is the SGC pursuit of structures and chemical probes. Our group collaborates closely within the whole SGC, enabling massively parallel crystallization of all purified proteins using our general-access infrastructure, and ensuring that crystals are solved by in-house testing, synchrotron data collection and rapid structure solution – an ideal environment for methods development.
Our scientific focus is how crystallography can truly transform cost and efficiency in protein-targeted chemistry – possible in principle, but difficult to achieve in practice. We thus address the methodology of: (1) ease-of-use and accessibility for all steps in crystallography, from crystallization to structure solution; and hence, (2) how to generate ligand-bound structures reliably and rapidly, to allow crystallography to become a truly routine assay for ligand binding.
The PX group offers opportunities both in structure projects, to gain extensive experience rapidly; and in developing methodologies, including: characterization of protein quality; calculating protein crystallizability; crystal optimization; non-manual harvesting of crystals; serial optimized data collection; massively parallelized structure solution; ligand solubility and crystal soaking protocols.
- Hugely speeds up dewar loading: unipucks can be placed directly into dewar (no lids!)
- Reduces pin frosting: surface ice is washed off
- Easier troubleshooting: Samsung programs rewritten to give debug information
We have a few surplus, information available on request.
- Excel-based design tool - rapid design and experiment review
- Direct interface to Perkin Elmer liquid handler (MPII)
- Direct interface to LIMS database (at SGC: BeeHive)
- Direct interface to stock management system (Acess)
- Low maintenance (probably)
Longer view
The context of our research is the SGC pursuit of structures and chemical probes: compounds that bind potently and selectively to defined proteins, and are thereby invaluable tools for untangling gene function in vivo.
The Protein Crystallography group (PX) collaborates closely within the whole SGC, enabling massively parallel crystallization of all purified protein using our general-access infrastructure, and ensuring that crystals are subsequently solved by in-house testing, synchrotron data collection and rapid structure solution. The environment is ideal for methods development, with large numbers of samples that are both diverse and medically relevant, including extensive experimental information captured in the laboratory information system (LIMS).
The scientific focus of the PX group is the question of how protein crystallography can truly transform cost and efficiency in protein-targeted chemistry. Strikingly, although structures are in principle powerful starting points for chemical design, and despite the availability of tens of thousands of protein structures, in practice this does not seem to have reduced the cost and effort required to develop targeted chemistry; indeed, the availability of a structure is not necessarily seen as essential in medicinal chemistry.
Our research topic is the methodology around this question: (1) how to transform the efficiency, cost and accessibility of protein crystallography, by overhauling the ease-of-use of all steps from crystallization to structure solution; and hence, (2) how co-crystal structures can be reliably and rapidly generated, allowing crystallography to becomes a routine assay for ligand binding and thereby integral to protein-targeted chemistry.
In detail, our approach is to implement and validate process engineering principles to the process: to provide rapid readout of success/failure for all stages, a common principle applies to all experimental and computational steps, namely efficient automation of mundane tasks, so that complex, non-automatable decisions are turned into relatively trivial ones. The latter requires carefully-designed software interfaces and real-time data mining to allow complex relationships to be quickly identified; but once achieved will make experiments easy to teach to non-experts, and moreover allow decision to be captured for future learning. Automation is developed through collaboration with engineers in industry and academia, while software is developed in the group.
The PX group offers both opportunities for crystallography projects and thereby gain extensive experience very rapidly; and to work on aspects of methodology spanning the entire process, including: characterization of protein quality; empirical calculation of crystallizability; discovery of alternative crystal forms; non-manual harvesting of crystals; serial data collection and processing; massively parallelized structure solution; ligand solubility and crystal soaking protocols.
