Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Letizia Chiodo, Thérèse E. Malliavin, Sergio Giuffrida, Luca Maragliano, Grazia Cottone

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Nicotinic acetylcholine receptors, belonging to the Cys-loop superfamily of ligand-gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists, and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understanding the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different nonconductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

Original languageEnglish
JournalJournal of Chemical Information and Modeling
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Nicotinic Receptors
Ligand-Gated Ion Channels
Ligands
structural model
simulation
Conformations
Conotoxins
interaction
Ions
Neurons
drug
Neurotransmitter Agents
Molecular dynamics
Membrane Proteins
present
experiment
Atoms
Computer simulation
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor : A Computational Study. / Chiodo, Letizia; Malliavin, Thérèse E.; Giuffrida, Sergio; Maragliano, Luca; Cottone, Grazia.

In: Journal of Chemical Information and Modeling, 01.01.2018.

Research output: Contribution to journalArticle

@article{8cee01f41aeb407aa8e6e912a013096a,
title = "Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study",
abstract = "Nicotinic acetylcholine receptors, belonging to the Cys-loop superfamily of ligand-gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists, and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understanding the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different nonconductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the {"}closed-locked{"} state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.",
author = "Letizia Chiodo and Malliavin, {Th{\'e}r{\`e}se E.} and Sergio Giuffrida and Luca Maragliano and Grazia Cottone",
year = "2018",
month = "1",
day = "1",
doi = "10.1021/acs.jcim.8b00412",
language = "English",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor

T2 - A Computational Study

AU - Chiodo, Letizia

AU - Malliavin, Thérèse E.

AU - Giuffrida, Sergio

AU - Maragliano, Luca

AU - Cottone, Grazia

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Nicotinic acetylcholine receptors, belonging to the Cys-loop superfamily of ligand-gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists, and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understanding the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different nonconductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

AB - Nicotinic acetylcholine receptors, belonging to the Cys-loop superfamily of ligand-gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists, and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understanding the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different nonconductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

UR - http://www.scopus.com/inward/record.url?scp=85056446853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056446853&partnerID=8YFLogxK

U2 - 10.1021/acs.jcim.8b00412

DO - 10.1021/acs.jcim.8b00412

M3 - Article

AN - SCOPUS:85056446853

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

ER -