Crystal structure analysis of a voltage-gated sodium channel

Lead Research Organisation: Birkbeck, University of London
Department Name: Biological Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Title advisor to national dance company on science-related performances for the public [continuing] 
Description "Stilled" performances at the Royal Festival Hall and Wellcome Collection based on crystallography - i was scientific advisor 
Type Of Art Performance (Music, Dance, Drama, etc) 
Year Produced 2011 
Impact contacts from other artists interested in science/art collaborations and contacts from the general public about performance. note that this is an ongoing activity 
 
Description crystal structure of the first open pore sodium channel, nature of binding of anaethetic, anti-epileptic and other off-target drugs to sodium channels that have lead to important new understanding of how these molecules work and implications for drug design
these have led both us and others to further investigate the design of new pharmaceuticals and have resulted in subsequent grant applications to the BBSRC and the National Instiute of Academic Anaesthetics, and the development of further collaborations between the UK and US
Sadly some exciting possible outcomes of this were not extended after Pfizer Neusentis closed down its operations
Exploitation Route we have extended them in future grants to examine drug interactions and disease-relatedness
Sectors Agriculture

Food and Drink

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

 
Description we have subsequently had collaborations with Pfizer Neusentis
First Year Of Impact 2014
Sector Pharmaceuticals and Medical Biotechnology
 
Title depostion of new crystal structure entries into the protein data bank (PDB) 
Description The PDB is the international standard data base for the deposition of crystal structures and the many crystal structures produced during this grant have been deposited for public access 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact increased understanding of drug interactions (including off-target interations of currently marketed drugs) 
 
Description School visit (Tonbridge schools science day) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Keynote speaker and poster judge at Tonbridge Area Schools Science day
Year(s) Of Engagement Activity 2019
 
Description annual talks for the public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact UCL Science Centre Friday Evening Discourses and Birkbeck SET Talks for the Public talks on science for the public (5th, 6th form, and public) annually and lecture/tour at the Wellcome Collection talks

no actual impacts realised to date
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020,2021
 
Description crystallography and culture 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact technical advisor for development of dance performances and "in residence" talks for the public on women in crystallography

the opera is the basis for funding applications to arts agencies
Year(s) Of Engagement Activity 2014
URL https://www.youtube.com/watch?v=8d0rpEdCTac
 
Description international advisory board (australia) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact international advisory board for scientific centre of excellence (australia)
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017