CICLO DE ESTUDOS - PROGRAMA DE PÓS-GRADUAÇÃO EM QUÍMICA
DIA : 15 de Abril de 2015 – Quarta-feira
LOCAL: Sala 11 Bloco Didático das Exatas do Departamento de Química da FFCLRP/USP
- ANFITEATRO
HORÁRIO: 16 horas 45 min.
Structure, Function and Drug Interactions in Voltage-Gated
Sodium Channels
Professor Bonnie Ann Wallace
Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, U.K.
RESUMO: The initiation of the action potential in excitable cells results from the opening of
voltage-gated sodium channels. In humans, mutations in sodium channels produce a wide range of
neurological and cardiovascular diseases; therefore these channels represent key targets for
development of pharmaceutical drugs. Sodium channels are also present in some prokaryotes,
where they function in homeostasis, motility, and chemotaxis. All sodium channels undergo a series
of conformational changes associated with their open, closed and inactivated functional states.
We have determined the crystal structure of the open conformation of the NavMs bacterial sodium
channel1. Comparisons between this structure and the structure of the closely-related NavAb
channel in the closed state reveal the mechanism of channel gating. Using a combination of
crystallography and spectroscopic methods (Synchrotron Radiation Circular Dichroism2 and
DEER-EPR3) and molecular dynamics calculations4, the structure of the C-terminal domain (not
visible in any of the previous crystal structures, but critical for full functioning of the channel) has
also been determined; its flexibility is compatible with an opening mechanism that does not
destabilise the tetrameric cytoplasmic domain coiled-coiled bundle.
Recently, we have shown that drugs which block eukaryotic sodium channels also bind to and block
the NavMs channel. Crystallographic, computational, spectroscopic and electrophysiology methods
have shown the structural and functional effects and locations of these blockers within the channel
cavity. The relative affinities and effects of a series of related and unrelated channel blockers were
determined. The binding sites identified were then validated by mutational studies. The affinities of
the drugs are remarkably similar for the NavMs and human Nav1.1 channels, which is valuable
information for the design of more specific and selective drugs and insecticides.
REFERÊNCIAS:
1McCusker, E.C., Bagnéris, C., Naylor, C.E., Cole, A.R., D’Avanzo, N., Nichols, C.G., and Wallace,
B.A. (2012) Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of
opening and closing. Nature Communications 3:1102.
2 Powl, A.M., O’Reilly, A.O., Miles, A.J. and Wallace, B.A. (2010) Synchrotron radiation circular
dichroism spectroscopy-defined structure of the C-terminal domain of NaChBac and its role in
channel assembly. Proc. Natl. Acad. Sci. USA, 107:14064-14069.
3Bagnéris, C., DeCaen, P.G., Hall, B.A., Naylor, C.E., Clapham, D.E., Kay, C.W.M., Wallace, B.A.
(2013) Role of the C-terminal domain in the structure and function of tetrameric sodium channels,
Nature Communications 4:2645.
4Ulmschneider,
M.B., Bagnéris, C., McCusker, E.C., DeCaen, P.G., Delling, M., Clapham, D.E.,
Ulmschneider, J.P. and Wallace, B.A. (2013) Molecular dynamics of ion transport through the open
conformation of a bacterial voltage-gated sodium channel. Proc. Nat. Acad. Sci. USA 110:6364-6369.
OBS:
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com Lâmia ou através do e-mail dq-pg-quimica@ffclrp.usp.br ou fone (16) 3315-4385.
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