Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist

Author:

Ahuja Shivani1,Mukund Susmith1,Deng Lunbin2,Khakh Kuldip3,Chang Elaine3,Ho Hoangdung1,Shriver Stephanie1,Young Clint3,Lin Sophia3,Johnson J. P.3,Wu Ping1,Li Jun4,Coons Mary1,Tam Christine1,Brillantes Bobby1,Sampang Honorio1,Mortara Kyle1,Bowman Krista K.1,Clark Kevin R.5,Estevez Alberto1,Xie Zhiwei3,Verschoof Henry3,Grimwood Michael6,Dehnhardt Christoph6,Andrez Jean-Christophe6,Focken Thilo6,Sutherlin Daniel P.4,Safina Brian S.4,Starovasnik Melissa A.1,Ortwine Daniel F.4,Franke Yvonne1,Cohen Charles J.3,Hackos David H.2,Koth Christopher M.1,Payandeh Jian1

Affiliation:

1. Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA.

2. Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.

3. Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada.

4. Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.

5. Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.

6. Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada.

Abstract

A channel involved in pain perception Voltage-gated sodium (Nav) channels propagate electrical signals in muscle cells and neurons. In humans, Nav1.7 plays a key role in pain perception. It is challenging to target a particular Nav isoform; however, arylsulfonamide antagonists selective for Nav1.7 have been reported recently. Ahuja et al. characterized the binding of these small molecules to human Nav channels. To further investigate the mechanism, they engineered a bacterial Nav channel to contain features of the Nav1.7 voltage-sensing domain that is targeted by the antagonist and determined the crystal structure of the chimera bound to an inhibitor. The structure gives insight into the mechanism of voltage sensing and will enable the design of more-selective Nav channel antagonists. Science , this issue p. 10.1126/science.aac5464

Funder

National Institutes of Health

U.S. Department of Energy (DOE)

National Institute of General Medical Sciences

DOE Office of Biological and Environmental Research

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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