6flr
From Proteopedia
Super-open structure of the AMPAR GluA3 N-terminal domain
Structural highlights
Function[GRIA3_RAT] Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate (By similarity). Publication Abstract from PubMedIonotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain. Their dysfunction is implicated in many neurological disorders, rendering iGluRs potential drug targets. Here, we performed a systematic analysis of the druggability of two major iGluR subfamilies, using molecular dynamics simulations in the presence of drug-like molecules. We demonstrate the applicability of druggability simulations by faithfully identifying known agonist and modulator sites on AMPA receptors (AMPARs) and NMDA receptors. Simulations produced the expected allosteric changes of the AMPAR ligand-binding domain in response to agonist. We also identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), resulting from its unique conformational flexibility that we explored further with crystal structures trapped in vastly different states. In addition to providing an in-depth analysis into iGluR NTD dynamics, our approach identifies druggable sites and permits the determination of pharmacophoric features toward novel iGluR modulators. Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.,Lee JY, Krieger J, Herguedas B, Garcia-Nafria J, Dutta A, Shaikh SA, Greger IH, Bahar I Structure. 2018 Nov 3. pii: S0969-2126(18)30378-2. doi:, 10.1016/j.str.2018.10.017. PMID:30528594[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
