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An international consortium of scientists has determined the structure of an important new drug target in complex with a synthetic molecule, opening up new avenues for drug discovery.

The enzyme SHIP2, which plays a major role in cell signalling, has attracted particular attention due to its role in the negative regulation of insulin signalling and is thought to be involved in type-2 diabetes, obesity and cancer. Previous attempts to crystallise the enzyme with its natural substrate were unsuccessful, so scientists at the University of Bath designed a new synthetic inhibitor as a mimic and with their European colleagues solved the X-ray crystal structure of a key fragment of SHIP2 bound to this compound.

The research, recently published in the leading international journal ACS Chemical Biology, was a collaborative project carried out by an international group of scientists based at the Karolinska Institutet in Stockholm Sweden, Nanyang University Singapore, the Université Libre de Bruxelles in Belgium and the University of Bath.

The scientists also undertook computational molecular dynamics on the complex, and discovered a flexible loop region of the protein that may close over the compound during binding. The researchers hope that targeting such a closed complex could provide a new strategy for the design of small-molecule drugs against SHIP2.

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