Crystal structure analysis of a voltage-gated sodium channel

Voltage-gated sodium channels (VGSC) are essential proteins enabling the transport of ions across cell membranes. They are found in all eukaryotic organisms and a range of bacteria. In humans as well as lower eukaryotes they are essential for normal functioning, and in higher organisms various isoforms are found in different tissues, ranging from heart to brain, with different functional roles in the healthy organism. Sodium channel mutations give rise to a number of disease states; as a result they are the targets of many pharmaceutical drugs, including ones for treatment of epilepsy and chronic pain. This proposal is to determine the crystal structure of a sodium channel, characterise its functional and binding properties, as a basis for understanding the structural basis of sodium channel functioning and its interactions with ligands, including drugs and insecticides.

Voltage-gated sodium channels are important elements in a wide range of biological systems, including neurotransmission and ion channel signaling, and are the targets of a number of current pharmaceuticals, despite there being very limited structural information relating to the molecular basis of their functioning. The aim of this proposal is to determine the crystal structure, as well as the functional properties of a sodium channel, and then use this for the design of mutants and the rational design of new compounds which could act as specific pharmaceutical agents or insecticides.

The potential public and economic impacts of this research are manifold, because voltage-gated sodium channels (VGSCs) are essential components in human health and in agriculture. Impact on the Public: An essential aspect of 'quality of life' is the ability to live pain-free. Sodium channels are causally associated with pain perception in humans and are currently the targets of a number of marketed pharmaceuticals. The availability for the first time of a crystal structure of a VGSC should have a major impact on the design and development of new drugs to treat pain, and hence directly on the quality of life of the general public. In addition, the ability to more efficiently produce crops not destroyed by insects, but with more specifically-targeted insecticides that do not harm either humans or plants, would also have a major quality of life factor in the ability to produce crops more effectively without harmful side effects to farmers and the environment. Impact on the Economy: The pharmaceutical market for specific and highly efficacious sodium channel inhibitors/modulators is enormous, because the potential number of people with either chronic or acute pain is vast. It is for this reason that many (most) of the world - and in particular, UK - big pharma companies, as well as many smaller biotech companies have active programmes for the development of VGSC-targeting drugs. To date, without a crystal structure of a VGSC on which to base rational design, most work has been through traditional pharma development cycles. However the availability of a crystal structure should have a dramatic impact on the initial and refinement phases of new drug design for these targets. Other sodium channels isoforms are the targets of other pharmaceuticals, notably those for treatment of epilepsy and certain cardiovascular diseases. Hence, drug company development programmes in these areas should also benefit from the availability of a crystal structure, especially as it should enable comparative modelling studies of homologues to better enable specific targeting for treatments without side effects resulting from broad-based sodium channel inhibitors with both neurological and cardiac muscle interactions. Another less quantifiable economic impact is the ability to keep members of the public in work. Chronic pain is often a disabling factor that can prevent or curtail employment; in providing background information that can lead to the development of new pain medications, this could contribute to maintaining normal function in many members of the population, including the ability to be gainfully employed, which would have an economic as well as a social impact. Likewise, the worldwide (and UK) market for insecticides is vast, and the ability to provide input into the development of new products that would specifically target insect pests (including those resistant to conventional insecticides such as DDT and pyrethroids) could have direct economic impact in terms of both marketable products by the agrifood business, and the more efficient, safer and cheaper production of food for the consuming public.