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Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2.

Frandsen A, Pickering DS, Vestergaard B, Kasper C, Nielsen BB, Greenwood JR, Campiani G, Fattorusso C, Gajhede M, Schousboe A, Kastrup JS
Mol Pharmacol 67 703-13 (2005)
Related entries: 1syh, 1xhy

Cited: 32 times
EuropePMC logo PMID: 15591246

Abstract

Ionotropic glutamate receptors mediate most rapid excitatory synaptic transmission in the mammalian central nervous system, and their involvement in neurological diseases has stimulated widespread interest in their structure and function. Despite a large number of agonists developed so far, few display selectivity among (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA)-receptor subtypes. The present study provides X-ray structures of the glutamate receptor 2 (GluR2)-selective partial agonist (S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl) propanoic acid [(S)-CPW399] in complex with the ligand-binding core of GluR2 (GluR2-S1S2J) and with a (Y702F)GluR2-S1S2J mutant. In addition, the structure of the nonselective partial agonist kainate in complex with (Y702F)GluR2-S1S2J was determined. The results show that the selectivity of (S)-CPW399 toward full-length GluR2 relative to GluR3 is reflected in the binding data on the two soluble constructs, allowing the use of (Y702F)GluR2-S1S2J as a model system for studying GluR2/GluR3 selectivity. Structural comparisons suggest that selectivity arises from disruption of a water-mediated network between ligand and receptor. A D1-D2 domain closure occurs upon agonist binding. (S)-CPW399 and kainate induce greater domain closure in the Y702F mutant, indicating that these partial agonists here act in a manner more reminiscent of full agonists. Both kainate and (S)-CPW399 exhibited higher efficacy at (Y702F)GluR2(Q)i than at wild-type GluR2(Q)i. Whereas an excellent correlation exists between domain closure and efficacy of a range of agonists at full-length GluR2 determined by electrophysiology in Xenopus laevis oocytes, a direct correlation between agonist induced domain closure of (Y702F)GluR2-S1S2J and efficacy at the GluR3 receptor is not observed. Although it clearly controls selectivity, mutation of this residue alone is insufficient to explain agonist-induced conformational rearrangements occurring in this variant.

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  2. The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. Kasper C, Pickering DS, Mirza O, Olsen L, Kristensen AS, Greenwood JR, Liljefors T, Schousboe A, Wätjen F, Gajhede M, Sigurskjold BW, Kastrup JS. J Mol Biol 357 1184-1201 (2006)
  3. Partial agonism and antagonism of the ionotropic glutamate receptor iGLuR5: structures of the ligand-binding core in complex with domoic acid and 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid. Hald H, Naur P, Pickering DS, Sprogøe D, Madsen U, Timmermann DB, Ahring PK, Liljefors T, Schousboe A, Egebjerg J, Gajhede M, Kastrup JS. J Biol Chem 282 25726-25736 (2007)
  4. Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. Kaae BH, Harpsøe K, Kastrup JS, Sanz AC, Pickering DS, Metzler B, Clausen RP, Gajhede M, Sauerberg P, Liljefors T, Madsen U. Chem Biol 14 1294-1303 (2007)
  5. Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists. Gill A, Birdsey-Benson A, Jones BL, Henderson LP, Madden DR. Biochemistry 47 13831-13841 (2008)
  6. Ligand-induced conformational changes in a thermophilic ribose-binding protein. Cuneo MJ, Beese LS, Hellinga HW. BMC Struct Biol 8 50 (2008)
  7. Rigid body essential X-ray crystallography: distinguishing the bend and twist of glutamate receptor ligand binding domains. Bjerrum EJ, Biggin PC. Proteins 72 434-446 (2008)
  8. Binding site flexibility: molecular simulation of partial and full agonists within a glutamate receptor. Arinaminpathy Y, Sansom MS, Biggin PC. Mol Pharmacol 69 11-18 (2006)
  9. Distinct structural features of cyclothiazide are responsible for effects on peak current amplitude and desensitization kinetics at iGluR2. Hald H, Ahring PK, Timmermann DB, Liljefors T, Gajhede M, Kastrup JS. J Mol Biol 391 906-917 (2009)
  10. N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands. Clausen RP, Christensen C, Hansen KB, Greenwood JR, Jørgensen L, Micale N, Madsen JC, Nielsen B, Egebjerg J, Bräuner-Osborne H, Traynelis SF, Kristensen JL. J Med Chem 51 4179-4187 (2008)
  11. Binding site and interlobe interactions of the ionotropic glutamate receptor GluK3 ligand binding domain revealed by high resolution crystal structure in complex with (S)-glutamate. Venskutonytė R, Frydenvang K, Gajhede M, Bunch L, Pickering DS, Kastrup JS. J Struct Biol 176 307-314 (2011)
  12. 3-hydroxypyridazine 1-oxides as carboxylate bioisosteres: a new series of subtype-selective AMPA receptor agonists. Greenwood JR, Mewett KN, Allan RD, Martín BO, Pickering DS. Neuropharmacology 51 52-59 (2006)
  13. Prediction of the receptor conformation for iGluR2 agonist binding: QM/MM docking to an extensive conformational ensemble generated using normal mode analysis. Sander T, Liljefors T, Balle T. J Mol Graph Model 26 1259-1268 (2008)
  14. A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: synthesis, resolution, pharmacology, and crystal structure. Szymańska E, Frydenvang K, Contreras-Sanz A, Pickering DS, Frola E, Serafimoska Z, Nielsen B, Kastrup JS, Johansen TN. J Med Chem 54 7289-7298 (2011)
  15. Quantifying water-mediated protein-ligand interactions in a glutamate receptor: a DFT study. Sahai MA, Biggin PC. J Phys Chem B 115 7085-7096 (2011)
  16. Pharmacological and structural characterization of conformationally restricted (S)-glutamate analogues at ionotropic glutamate receptors. Juknaitė L, Venskutonytė R, Assaf Z, Faure S, Gefflaut T, Aitken DJ, Nielsen B, Gajhede M, Kastrup JS, Bunch L, Frydenvang K, Pickering DS. J Struct Biol 180 39-46 (2012)
  17. A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors. Lima Neto JX, Fulco UL, Albuquerque EL, Corso G, Bezerra EM, Caetano EW, da Costa RF, Freire VN. Phys Chem Chem Phys 17 13092-13103 (2015)
  18. Molecular mechanism of agonist recognition by the ligand-binding core of the ionotropic glutamate receptor 4. Kasper C, Frydenvang K, Naur P, Gajhede M, Pickering DS, Kastrup JS. FEBS Lett 582 4089-4094 (2008)
  19. L-Asp is a useful tool in the purification of the ionotropic glutamate receptor A2 ligand-binding domain. Krintel C, Frydenvang K, Ceravalls de Rabassa A, Kaern AM, Gajhede M, Pickering DS, Kastrup JS. FEBS J 281 2422-2430 (2014)
  20. Molecular details of ligand selectivity determinants in a promiscuous β-glucan periplasmic binding protein. Munshi P, Stanley CB, Ghimire-Rijal S, Lu X, Myles DA, Cuneo MJ. BMC Struct Biol 13 18 (2013)
  21. (+)-(S)-trujillon, (+)-(S)-4-(2,2-diphenyl-1,3,2-oxazabolidin-5-oxo)propionic acid, a novel glutamatergic analog, modifies the activity of globus pallidus neurons by selective NMDA receptor activation. Araujo-Alvarez JM, Trujillo-Ferrara JG, Ponce-Franco D, Correa-Basurto J, Delgado A, Querejeta E. Chirality 23 429-437 (2011)


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