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
N1 - Funding Information:
Supported by USPHS grants: UO-1 NS058046 and R37 GM18360.
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
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U2 - 10.1016/j.bcp.2007.07.038
DO - 10.1016/j.bcp.2007.07.038
M3 - Article
C2 - 17826748
AN - SCOPUS:34548672882
SN - 0006-2952
VL - 74
SP - 1164
EP - 1171
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 8
ER -