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Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding Sites02:40

Ligand Binding Sites

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Assembly of Signaling Complexes01:30

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:

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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

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Structural insights into Cys-loop receptor function and ligand recognition.

Mieke Nys1, Divya Kesters, Chris Ulens

  • 1Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PB 601, B-3000 Leuven, Belgium.

Biochemical Pharmacology
|July 16, 2013
PubMed
Summary

Pentameric ligand-gated ion channels (pLGICs) are crucial for neurotransmission. Recent structural and simulation data reveal key mechanisms in ligand recognition, channel gating, and ion permeation for these drug targets.

Keywords:
Channel gatingCys-loop receptorIon permeationLigand recognitionPentameric ligand-gated ion channel

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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Method for Efficient Refolding and Purification of Chemoreceptor Ligand Binding Domain
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Method for Efficient Refolding and Purification of Chemoreceptor Ligand Binding Domain

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Method for Efficient Refolding and Purification of Chemoreceptor Ligand Binding Domain

Published on: December 12, 2017

Area of Science:

  • Neuroscience
  • Structural Biology
  • Biophysics

Background:

  • Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission.
  • Dysfunction of pLGICs is linked to various diseases, making them important drug targets.
  • Key pLGIC subtypes include GABA(A), GABA(C), glycine, 5-HT3 serotonin, and nicotinic acetylcholine (nACh) receptors.

Purpose of the Study:

  • To review recent advances in understanding ligand recognition, channel gating, and ion permeation in pLGICs.
  • To integrate structural, electrophysiological, and simulation data for a comprehensive view.
  • To highlight the structural determinants of pLGIC function.

Main Methods:

  • X-ray crystallography of ligand-binding proteins and integral pLGICs (ELIC, GluCl).
  • Electrophysiological recordings to study channel function.
  • Molecular dynamic simulations to analyze receptor behavior.
  • Analysis of structural rearrangements in ligand-binding and pore-forming domains.

Main Results:

  • A conserved cation-π interaction is critical for ligand recognition in pLGICs.
  • Structural rearrangements in loop C and F of the extracellular domain influence channel gating.
  • Distinct conformational states of the pore-forming domain (open vs. closed) have been identified in crystal structures.
  • Key determinants of ion selection and permeation have been elucidated.

Conclusions:

  • Structural insights combined with functional data provide a detailed mechanistic understanding of pLGIC operation.
  • The findings offer a structural basis for rational drug design targeting pLGICs.
  • Further research can build upon these structural views to explore ion channel modulation.