Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

Todd T. Talley, Michal Harel, Ryan E. Hibbs, Zoran Radić, Motohiro Tomizawa, John E. Casida, Palmer Taylor

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 Å in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

Original languageEnglish (US)
Pages (from-to)7606-7611
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number21
DOIs
StatePublished - May 27 2008

Fingerprint

Cholinergic Agonists
Nicotinic Receptors
Carrier Proteins
Acetylcholine
Ligands
Insects
Binding Sites
Nicotinic Agonists
Nicotinic Antagonists
Aplysia
Mollusca
Insecticides
Tryptophan
Fluorescence
Amino Acids
Proteins

Keywords

  • Acetylcholine-binding protein
  • Crystal structure
  • Imidacloprid
  • Nicotinic receptor
  • Thiacloprid

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Atomic interactions of neonicotinoid agonists with AChBP : Molecular recognition of the distinctive electronegative pharmacophore. / Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radić, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 21, 27.05.2008, p. 7606-7611.

Research output: Contribution to journalArticle

Talley, Todd T. ; Harel, Michal ; Hibbs, Ryan E. ; Radić, Zoran ; Tomizawa, Motohiro ; Casida, John E. ; Taylor, Palmer. / Atomic interactions of neonicotinoid agonists with AChBP : Molecular recognition of the distinctive electronegative pharmacophore. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 21. pp. 7606-7611.
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