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Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

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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...
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Conserved Binding Sites01:49

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Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
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G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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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.
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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Related Experiment Video

Updated: Nov 19, 2025

Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
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Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions

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Predictable cholesterol binding sites in GPCRs lack consensus motifs.

Geoffrey J Taghon1, Jacob B Rowe1, Nicholas J Kapolka1

  • 1Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, RMSB 6078A, Miami, FL 33136, USA.

Structure (London, England : 1993)
|January 28, 2021
PubMed
Summary

Cholesterol binding sites on human G protein-coupled receptors (GPCRs) are predictable and consistent across experimental methods. Most sites lack specific binding motifs, suggesting a general interaction rather than specialized recognition.

Keywords:
G protein-coupled receptors (GPCRs)X-ray diffractioncholesterolcholesterol consensus motif (CCM)cholesterol recognition/interaction amino acid consensus (CRAC) motifcryo-electron microscopy (cryo-EM)lipidsstructural informatics

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Construction of Model Lipid Membranes Incorporating G-protein Coupled Receptors GPCRs

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Area of Science:

  • Structural Biology
  • Biochemistry
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are crucial transmembrane proteins involved in cellular signaling.
  • GPCRs represent the largest and most therapeutically targeted receptor class in humans, with over 800 identified members.
  • Advances in X-ray diffraction and cryo-electron microscopy (cryo-EM) have yielded numerous GPCR structures, many stabilized by cholesterol.

Purpose of the Study:

  • To investigate the recurring motifs and patterns of cholesterol binding in human GPCR structures.
  • To determine if cholesterol binding patterns differ between structures obtained via X-ray crystallography and cryo-EM.
  • To comprehensively analyze the location and composition of cholesterol binding sites across a large dataset of human GPCR structures.

Main Methods:

  • Comprehensive analysis of 473 human GPCR structural chains.
  • Detailed examination of the location and composition of identified cholesterol binding sites.
  • Comparative analysis of cholesterol binding in structures determined by X-ray diffraction versus cryo-EM.

Main Results:

  • Cholesterol binding sites exhibit similar characteristics in both cryo-EM and X-ray structures.
  • A significant majority (92%) of cholesterol molecules on GPCR surfaces are located in predictable positions.
  • These predictable cholesterol binding locations generally lack discernible, specific cholesterol-binding motifs.

Conclusions:

  • Cholesterol interaction with GPCRs is largely conserved across different experimental techniques.
  • The binding of cholesterol to GPCRs appears to be driven by general surface properties rather than specific recognition motifs.
  • Understanding these predictable cholesterol binding sites could inform future drug design targeting GPCRs.