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Related Concept Videos

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

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 and Linkage00:49

Ligand Binding and Linkage

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 the...
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...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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...

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Related Experiment Video

Updated: Jun 23, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Dynamically driven ligand selectivity in cyclic nucleotide binding domains.

Rahul Das1, Somenath Chowdhury, Mohammad T Mazhab-Jafari

  • 1Department of Chemistry, McMaster University, Hamilton, Ontario L8S 4M1, Canada.

The Journal of Biological Chemistry
|May 1, 2009
PubMed
Summary

Researchers explored how protein kinase A (PKA) and EPAC selectively bind cAMP over cGMP. Differences in ligand binding and allostery reveal distinct molecular mechanisms for signaling pathway selectivity.

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Last Updated: Jun 23, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library
10:17

Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library

Published on: January 14, 2020

Area of Science:

  • Molecular biology
  • Biochemistry
  • Cell signaling

Background:

  • Aberrant cross-talk between cAMP and cGMP signaling pathways is minimized by the selectivity of cAMP binding domains (CBDs).
  • Protein kinase A (PKA) and EPAC are critical eukaryotic cAMP receptors with distinct mechanisms for cAMP versus cGMP selectivity.
  • PKA selectivity is mainly controlled by ligand affinity, while EPAC selectivity is determined by allostery.

Purpose of the Study:

  • To comparatively analyze the cGMP-bound states of PKA and EPAC CBDs using NMR.
  • To elucidate the molecular basis for distinct cAMP/cGMP selectivity mechanisms in PKA and EPAC.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Comparative analysis of cGMP-bound states of PKA and EPAC CBDs

Main Results:

  • cGMP binds to PKA CBD in a syn conformation, causing steric clashes and reduced affinity.
  • cGMP binds to EPAC CBD in an anti conformation, inducing perturbations and dynamic changes in the ionic latch region.
  • Significant structural changes were not observed in EPAC CBD, but dynamics differed between cAMP- and cGMP-bound states.

Conclusions:

  • Distinct molecular mechanisms underlie cGMP antagonism in PKA and EPAC.
  • Allostery plays a pivotal role in signaling selectivity through dynamic changes, even without significant affinity variations.
  • Understanding these differences is crucial for comprehending cAMP and cGMP signaling pathway regulation.