To function properly, proteins must adopt particular three-dimensional structures. By elucidating protein structures, or even just the conformation of single amino acids, researchers can often deduce how proteins work in the body – and therefore begin designing or refining drugs to modify protein activity and, hopefully, treat or prevent disease.

Dr Sarah Lummis (University of Cambridge) and colleagues, for example, have discovered how a neurotransmitter receptor (5-HT3), an ion channel, is opened and closed. The mechanism depends on the conformation of a single proline in a 'hinge' region of the receptor. In one conformation the channel is open; in the other it is closed.

Myosin 5 transports material around the cell, by 'walking' along actin fibres. Dr Peter Knight at the University of Leeds and colleagues have found that, without any bound cargo, myosin 5's long tail domains fold up with its motor domains, and this globular form binds weakly to actin. When its cargo binds, the structure unfolds, the motor domains attach to actin, and the myosin 5 begins its walk.

The structure of Hsp90, determined by Professor Laurence Pearl (Institute of Cancer Research) and colleagues, has revealed a complex set of rearrangements that enable Hsp90 to bind and activate its target proteins. Since Hsp90 is needed to activate proteins driving proliferation in many cancer cells, drugs that block Hsp90 hold promise as anticancer therapies.

Finally, among much research facilitated by the Structural Genomics Consortium, Dr Udo Oppermann and colleagues have discovered how anti-osteoporosis drugs, bisphosphonates, bind to their target enzymes – opening up the prospect of more finely tailored drugs.

Image: Key amino acids in the 5-HT3 receptor; Sarah Lummis

External links

• Ali MM et al. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 2006;440(7087):1013–7.
• Lummis SC et al. Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 005;438(7065):248–52.
• Thirumurugan K et al. The cargo-binding domain regulates structure and activity of myosin 5. Nature 2006;442(7099):212–5.
• Kavanagh KL et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci USA 2006;103(20):7829–34.

The Structural Genomics Consortium is a not-for-profit organisation that aims to determine the three-dimensional structures of proteins of medical relevance, and place them in the public domain without restriction. It is supported by the Wellcome Trust and a range of public and private sources in the UK, Canada and Sweden.