Structure-guided drug design

Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

Palmer Taylor, Todd T. Talley, Zoran Radic', Scott B. Hansen, Ryan E. Hibbs, Jian Shi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Neuronal nicotinic receptors, encoded by nine genes of the α and three of the β type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholine-binding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional non-competitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.

Original languageEnglish (US)
Pages (from-to)1164-1171
Number of pages8
JournalBiochemical Pharmacology
Volume74
Issue number8
DOIs
StatePublished - Oct 15 2007

Fingerprint

Drug Design
Nicotinic Receptors
Carrier Proteins
Ligands
Molecules
Pharmaceutical Preparations
Acetylcholine
Marine Toxins
Click Chemistry
Crystallography
Genes
Mollusca
Terpenes
Alkaloids
Peptides
Association reactions
Proteins

Keywords

  • Acetylcholine-binding protein
  • Allosteric modulators
  • Channel vestibule
  • Competitive ligand site
  • Crystal structure
  • Fluorescence anisotropy
  • Freeze-frame click chemistry
  • Isotope exchange
  • Nicotinic receptor structure

ASJC Scopus subject areas

  • Pharmacology

Cite this

Structure-guided drug design : Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes. / Taylor, Palmer; Talley, Todd T.; Radic', Zoran; Hansen, Scott B.; Hibbs, Ryan E.; Shi, Jian.

In: Biochemical Pharmacology, Vol. 74, No. 8, 15.10.2007, p. 1164-1171.

Research output: Contribution to journalArticle

Taylor, Palmer ; Talley, Todd T. ; Radic', Zoran ; Hansen, Scott B. ; Hibbs, Ryan E. ; Shi, Jian. / Structure-guided drug design : Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes. In: Biochemical Pharmacology. 2007 ; Vol. 74, No. 8. pp. 1164-1171.
@article{637f53fb18aa4638905d6987732db544,
title = "Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes",
abstract = "Neuronal nicotinic receptors, encoded by nine genes of the α and three of the β type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholine-binding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional non-competitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.",
keywords = "Acetylcholine-binding protein, Allosteric modulators, Channel vestibule, Competitive ligand site, Crystal structure, Fluorescence anisotropy, Freeze-frame click chemistry, Isotope exchange, Nicotinic receptor structure",
author = "Palmer Taylor and Talley, {Todd T.} and Zoran Radic' and Hansen, {Scott B.} and Hibbs, {Ryan E.} and Jian Shi",
year = "2007",
month = "10",
day = "15",
doi = "10.1016/j.bcp.2007.07.038",
language = "English (US)",
volume = "74",
pages = "1164--1171",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Structure-guided drug design

T2 - Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

AU - Taylor, Palmer

AU - Talley, Todd T.

AU - Radic', Zoran

AU - Hansen, Scott B.

AU - Hibbs, Ryan E.

AU - Shi, Jian

PY - 2007/10/15

Y1 - 2007/10/15

N2 - Neuronal nicotinic receptors, encoded by nine genes of the α and three of the β type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholine-binding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional non-competitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.

AB - Neuronal nicotinic receptors, encoded by nine genes of the α and three of the β type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholine-binding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional non-competitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.

KW - Acetylcholine-binding protein

KW - Allosteric modulators

KW - Channel vestibule

KW - Competitive ligand site

KW - Crystal structure

KW - Fluorescence anisotropy

KW - Freeze-frame click chemistry

KW - Isotope exchange

KW - Nicotinic receptor structure

UR - http://www.scopus.com/inward/record.url?scp=34548672882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548672882&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2007.07.038

DO - 10.1016/j.bcp.2007.07.038

M3 - Article

VL - 74

SP - 1164

EP - 1171

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 8

ER -