Download MendeleyA conformational intermediate in glutamate receptor activation.
Lau, A.Y., Salazar, H., Blachowicz, L., Ghisi, V., Plested, A.J., Roux, B.(2013) Neuron 79: 492-503
- PubMed: 23931998
- DOI: https://doi.org/10.1016/j.neuron.2013.06.003
- Primary Citation of Related Structures:
4L17 - PubMed Abstract:
Ionotropic glutamate receptors (iGluRs) transduce the chemical signal of neurotransmitter release into membrane depolarization at excitatory synapses in the brain. The opening of the transmembrane ion channel of these ligand-gated receptors is driven by conformational transitions that are induced by the association of glutamate molecules to the ligand-binding domains (LBDs). Here, we describe the crystal structure of a GluA2 LBD tetramer in a configuration that involves an ∼30° rotation of the LBD dimers relative to the crystal structure of the full-length receptor. The configuration is stabilized by an engineered disulfide crosslink. Biochemical and electrophysiological studies on full-length receptors incorporating either this crosslink or an engineered metal bridge show that this LBD configuration corresponds to an intermediate state of receptor activation. GluA2 activation therefore involves a combination of both intra-LBD (cleft closure) and inter-LBD dimer conformational transitions. Overall, these results provide a comprehensive structural characterization of an iGluR intermediate state.
Organizational Affiliation:
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. [email protected]
