期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 16, 页码 6814-6819出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811899106
关键词
glutamate receptor; ion channel; optics; photoswitch
资金
- Human Frontiers Science Program [RGP23-2005]
- National Institutes of Health (NIH) Nanomedicine Development Center [PN2 EY018241]
- Japan Society for the Promotion of Science
- Institute of Tokyo Vascular Disease
- Generalitat de Catalunya (Nanotechnology Program)
- Ministerio de Educacion y Ciencia (Spain)
- Human Frontiers Science Program
- Novartis and Roche Biosciences
- NIH [GM-62342]
Photoswitched tethered ligands (PTLs) can be used to remotely control protein function with light. We have studied the geometric and conformational factors that determine the efficacy of PTL gating in the ionotropic glutamate receptor iGluR6 using a family of photoiosomerizable MAG (maleimide-azobenzene-glutamate) PTLs that covalently attach to the clamshell ligand-binding domain. Experiments and molecular dynamics simulations of the modified proteins show that optical switching depends on 2 factors: (i) the relative occupancy of the binding pocket in the 2 photoisomers of MAG and (ii) the degree of clamshell closure that is possible given the disposition of the MAG linker. A synthesized short version of MAG turns the channel on in either the cis or trans state, depending on the point of attachment. This yin/yang optical control makes it possible for 1 wavelength of light to elicit action potentials in one set of neurons, while deexciting a second set of neurons in the same preparation, whereas a second wavelength has the opposite effect. The ability to generate opposite responses with a single PTL and 2 versions of a target channel, which can be expressed in different cell types, paves the way for engineering opponency in neurons that mediate opposing functions.
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