5H8N

Structure of the human GluN1/GluN2A LBD in complex with NAM

Summary for 5H8N

• Entry DOI: 10.2210/pdb5h8n/pdb
• Related: 5H8F 5H8H 5H8Q 5H8R 5H8S
• Descriptor: Glutamate receptor ionotropic, NMDA 2A,Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1,Glutamate receptor ionotropic, NMDA 1, GLUTAMIC ACID, ... (7 entities in total)
• Functional Keywords: glun1, glun2a, nmda, receptor, transport protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : Q12879 Q05586
• Total number of polymer chains: 2
• Total formula weight: 65954.23

Authors

Wallweber, H.J.A.,Lupardus, P.J. (deposition date: 2015-12-23, release date: 2016-02-24, Last modification date: 2024-11-20)

Primary citation

Hackos, D.H.,Lupardus, P.J.,Grand, T.,Chen, Y.,Wang, T.M.,Reynen, P.,Gustafson, A.,Wallweber, H.J.,Volgraf, M.,Sellers, B.D.,Schwarz, J.B.,Paoletti, P.,Sheng, M.,Zhou, Q.,Hanson, J.E.
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
Neuron, 89:983-999, 2016

PubMed Abstract: To enhance physiological function of NMDA receptors (NMDARs), we identified positive allosteric modulators (PAMs) of NMDARs with selectivity for GluN2A subunit-containing receptors. X-ray crystallography revealed a binding site at the GluN1-GluN2A dimer interface of the extracellular ligand-binding domains (LBDs). Despite the similarity between the LBDs of NMDARs and AMPA receptors (AMPARs), GluN2A PAMs with good selectivity against AMPARs were identified. Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices from wild-type (WT), but not GluN2A knockout (KO), mice. Individual GluN2A PAMs exhibited variable degrees of glutamate (Glu) dependence, impact on NMDAR Glu EC50, and slowing of channel deactivation. These distinct PAMs also exhibited differential impacts during synaptic plasticity induction. The identification of a new NMDAR modulatory site and characterization of GluN2A-selective PAMs provide powerful molecular tools to dissect NMDAR function and demonstrate the feasibility of a therapeutically desirable type of NMDAR enhancement.

PubMed: 26875626
DOI: 10.1016/j.neuron.2016.01.016

Experimental method

X-RAY DIFFRACTION (2.5 Å)