Cambridge Healthtech Institute’s Kent Simmons recently spoke with Dr. Bonnie Wallace, an Associate Professor at the University of Leeds, about her upcoming Keynote presentation “The High-Resolution Crystal Structure of The NavMs Sodium Channel Provides Information on Drug Binding and Mutations Associated with Human Diseases,” to be delivered in the Antibodies Against Membrane Protein Targets (Part 1) meeting at the 2018 Discovery on Target. DOT is scheduled for September 25-28, 2018 in Boston, with Part 1 of the membrane proteins program set for September 26-27.

Have you established collaborations with companies in the past, and are you open to such collaborations in the future? What can academic/industrial partnerships offer to both parties?

Yes, I have found partnerships with companies to be very productive and beneficial for both parties and I personally have enjoyed the interactions and stimulation of working with industrial partners. Over the years we have worked with companies in many different ways: we have shared CASE PhD students or hosted visiting PhD students on company release, done studies with company-funded postdocs or ones supported by jointly-held grants, or as simple collaborations. Often companies have approached me based on our published work or work we have presented at meetings. I have also taken the opportunity at meetings such as this to contact companies with whom I think we may have a common interest. It is for these reasons that I have been keen to participate in such an exciting and broad-ranging meeting as DOT.

Your work on prokaryotic sodium channels has provided important information on their structure and function and drug binding, but how can they contribute to our understanding of eukaryotic sodium channels and their roles in disease and development of new pharmaceuticals (both small molecule and antibodies)?

Sodium channels are important targets for a wide range of channelopathies, including epilepsy, cardiovascular diseases and chronic neuropathic pain, which are the focus of many pharmaceutical development programs. Significantly, with collaborators, we have shown that the NavMs prokaryotic channel (the only full length open and active sodium channel whose structure has been determined by crystallography), has many identical or highly similar properties to human sodium channels, including sodium flux and selectivity, sequence identities (especially in functionally-critical regions), and drug binding affinities and kinetics. They have proven to be good testing grounds for drug development. As we have recently moved into cryoElectronMicroscopy studies of prokaryotic and human sodium channels, these should complement the higher resolution crystal structures of NavMs we already have in hand, and should open a new area for development in sodium channel research.

What are the prospects of developing new state-dependent drugs that bind to sodium channels?

Our new (unpublished) work which I will present at the DOT meeting at last shows that the transmembrane fenestrations originally proposed by Hille in 1972 do exist as entry point for drugs into the sodium channel hydrophobic cavities, thereby blocking ion translocation function. By comparing the structures of the open and closed intracellular gates, we have now shown that the size and shape of these fenestrations vary in the two states and hence could be exploited to enable entry to molecules of different sizes and shapes, thereby potentially leading to development of state-dependent drugs.

How do you see in silico studies complementing in vitro and in vivo studies on ion channels?

My lab uses molecular modelling and bioinformatics techniques in close juxtaposition with our biophysical and structural studies to give insight into novel features of sodium channels. Moreover, we have highly productive collaborations not only with electrophysiologists on the functional side, but also with molecular dynamics calculation experts to further exploit and extend our structural studies.

What other tools are you involved in developing for defining structure-function relationships of these and other membrane proteins?

My lab has had a very active program over the past 30 years in developing tools and resources and new methods for the characterization of proteins by circular dichroism spectroscopy, with a focus on applications complementary to structural studies and on applications associated with Higher Order Structure (HOS) characterizations for biopharmaceuticals

Speaker Biography:

Bonnie Ann Wallace, Ph.D., Professor, Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom

Bonnie Ann Wallace is Professor of Molecular Biophysics in the Institute of Structural and Molecular Biology at Birkbeck College, University of London. She obtained her PhD in Molecular Biophysics and Biochemistry from Yale University and did postdoctoral work (as a Jane Coffin Childs fellow) at Harvard and at the MRC Lab of Molecular Biology in Cambridge. She was an Associate Professor of Biochemistry at Columbia University, before moving to Rensselaer Polytechnic Institute as Professor of Chemistry and Director of the Center for Biophysics. She moved her lab permanently to London following a sabbatical visit (as a Fogarty Fellow) to Birkbeck. She was the first recipient of the Dayhoff Award of the U.S. Biophysical Society (for the best young female biophysicist in America), and received the Irma T. Hirschl Award, and the Camille and Henry Dreyfus Teacher-Scholar Award, and was previously named one of the dozen top young scientists in America by Fortune Magazine. She received the 2010 AstraZeneca Award from the Biochemical Society and the 2009 Interdisciplinary Prize from the Royal Society of Chemistry and last year was recently elected an Honorary Member of the British Biophysical Society and a Fellow of The (U.S.) Biophysical Society. Her principal research interests are in the structure and function of voltage-gated sodium channels, and the development of new methods and bioinformatics tools for characterising proteins.