TY - JOUR
T1 - Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics
AU - Yao, Yongneng
AU - Belcher, John
AU - Berger, Anthony J.
AU - Mayer, Mark L.
AU - Lau, Albert Y.
N1 - Funding Information:
We thank Barry Grant for helpful discussions on using the Bio3D package. Data were collected at the Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy under contract no. W-31-109-Eng-38. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH) and resources provided by the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation grant no. OCI-1053575. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (to M.L.M.) and NIH grant no. GM094495 (to A.Y.L.).
PY - 2013/10/8
Y1 - 2013/10/8
N2 - The NMDA receptor family of glutamate receptor ion channels is formed by obligate heteromeric assemblies of GluN1, GluN2, and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states unexpectedly reveal open- and closed-cleft conformations, respectively, with water molecules filling the binding pockets. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo-state LBDs sample closed-cleft conformations, suggesting that their agonists bind via a conformational selection mechanism. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggest binding of glutamate via an induced-fit mechanism. Principal component analysis reveals a rich spectrum of hinge bending, rocking, twisting, and sweeping motions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by glutamate receptor ion channels.
AB - The NMDA receptor family of glutamate receptor ion channels is formed by obligate heteromeric assemblies of GluN1, GluN2, and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states unexpectedly reveal open- and closed-cleft conformations, respectively, with water molecules filling the binding pockets. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo-state LBDs sample closed-cleft conformations, suggesting that their agonists bind via a conformational selection mechanism. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggest binding of glutamate via an induced-fit mechanism. Principal component analysis reveals a rich spectrum of hinge bending, rocking, twisting, and sweeping motions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by glutamate receptor ion channels.
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U2 - 10.1016/j.str.2013.07.011
DO - 10.1016/j.str.2013.07.011
M3 - Article
C2 - 23972471
AN - SCOPUS:84885433421
SN - 0969-2126
VL - 21
SP - 1788
EP - 1799
JO - Structure
JF - Structure
IS - 10
ER -