Structure-Based Drug Design will crystallisation ‘chaperones’ make all proteins crystallisable?

By Dr Chun-wa Chung

Fall 2009

Macromolecular x-ray crystallography is usually an integral part of small molecule drug discovery for soluble targets. Recent advances in the crystallography of membrane proteins, such as ion channels and G-protein-coupled receptors, have opened up the prospect of extending structure-based methods into these well validated target classes. The use of chaperone-assisted crystallisation has been a key feature of this success. This article explores the growing repertoire of crystallisation chaperones, examples of their success and how they may enhance the general structural tractability of many protein targets.

Protein crystallography has become an invaluable tool embedded within small molecule drug discovery programmes. It often provides important insights into the mode of action of the compounds and stimulates ideas on how their affinities, specificities and physical chemical properties may be optimised to make a drug-like molecule.

To determine x-ray complexes of a target protein with bound ligands it is necessary to fulfil a number of steps that can be simplistically summarised as protein production, protein crystallisation and x-ray structure determination. Advances in recombinant protein technologies and automation, coupled with wide access to intense in-house and external x-ray sources and improved computational methods, now allow rapid structure determination on a scale and speed previously unimaginable. In ideal cases, it has even been possible to use x-ray crystallography to screen small fragment libraries for lead generation efforts producing hundreds, if not thousands of datasets and structures. In reality, there are many factors that limit the number of targets for which this ideal scenario can be achieved. Attrition can occur at every step on the road to establishing a robust crystal system but the acknowledged bottleneck is protein crystallisation.....................