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Binding and selectivity of the marine toxin neodysiherbaine A and its synthetic analogues to GluK1 and GluK2 kainate receptors.

Unno M, Shinohara M, Takayama K, Tanaka H, Teruya K, Doh-ura K, Sakai R, Sasaki M, Ikeda-Saito M
J Mol Biol 413 667-83 (2011)
Related entries: 2znt, 2znu, 3fuz, 3fv1, 3fv2, 3fvg, 3fvk, 3fvn, 3qxm

Cited: 10 times
EuropePMC logo PMID: 21893069

Abstract

Dysiherbaine (DH) and neodysiherbaine A (NDH) selectively bind and activate two kainate-type ionotropic glutamate receptors, GluK1 and GluK2. The ligand-binding domains of human GluK1 and GluK2 were crystallized as bound forms with a series of DH analogues including DH, NDH, 8-deoxy-NDH, 9-deoxy-NDH and 8,9-dideoxy-NDH (MSVIII-19), isolated from natural sources or prepared by total synthesis. Since the DH analogues exhibit a wide range of binding affinities and agonist efficacies, it follows that the detailed analysis of crystal structure would provide us with a significant opportunity to elucidate structural factors responsible for selective binding and some aspects of gating efficacy. We found that differences in three amino acids (Thr503, Ser706 and Ser726 in GluK1 and Ala487, Asn690 and Thr710 in GluK2) in the ligand-binding pocket generate differences in the binding modes of NDH to GluK1 and GluK2. Furthermore, deletion of the C(9) hydroxy group in NDH alters the ligand conformation such that it is no longer suited for binding to the GluK1 ligand-binding pocket. In GluK2, NDH pushes and rotates the side chain of Asn690 (substituted for Ser706 in GluK1) and disrupts an interdomain hydrogen bond with Glu409. The present data support the idea that receptor selectivities of DH analogues resulted from the differences in the binding modes of the ligands in GluK1/GluK2 and the steric repulsion of Asn690 in GluK2. All ligands, regardless of agonist efficacy, induced full domain closure. Consequently, ligand efficacy and domain closure did not directly coincide with DH analogues and the kainate receptors.

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Reviews citing this publication (2)

  1. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Hansen KB, Wollmuth LP, Bowie D, Furukawa H, Menniti FS, Sobolevsky AI, Swanson GT, Swanger SA, Greger IH, Nakagawa T, McBain CJ, Jayaraman V, Low CM, Dell'Acqua ML, Diamond JS, Camp CR, Perszyk RE, Yuan H, Traynelis SF. Pharmacol Rev 73 298-487 (2021)
  2. Recent progress in neuroactive marine natural products. Sakai R, Swanson GT. Nat Prod Rep 31 273-309 (2014)

Articles citing this publication (6)

  1. 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)
  2. Correlating efficacy and desensitization with GluK2 ligand-binding domain movements. Nayeem N, Mayans O, Green T. Open Biol 3 130051 (2013)
  3. The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit. Fisher JL. Neuropharmacology 85 9-17 (2014)
  4. Molecular recognition of two 2,4-syn-functionalized (S)-glutamate analogues by the kainate receptor GluK3 ligand binding domain. Venskutonytė R, Larsen AP, Frydenvang K, Gajhede M, Sagot E, Assaf Z, Gefflaut T, Pickering DS, Bunch L, Kastrup JS. ChemMedChem 9 2254-2259 (2014)
  5. GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models. Martinez-Perez JA, Iyengar S, Shannon HE, Bleakman D, Alt A, Arnold BM, Bell MG, Bleisch TJ, Castaño AM, Del Prado M, Dominguez E, Escribano AM, Filla SA, Ho KH, Hudziak KJ, Jones CK, Mateo A, Mathes BM, Mattiuz EL, Ogden AM, Simmons RM, Stack DR, Stratford RE, Winter MA, Wu Z, Ornstein PL. Bioorg Med Chem Lett 23 6459-6462 (2013)
  6. A monocyclic neodysiherbaine analog: Synthesis and evaluation. Fukushima K, Ishikawa Y, Sakai R, Oikawa M. Bioorg Med Chem Lett 26 5164-5167 (2016)


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