Related Experiment Video
Updated: Aug 16, 2025
10:21
Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
Published on: February 23, 2024
2.8K
Portability of a Small-Molecule Binding Site between Disordered Proteins
Rajesh Jaiprashad1, Sachith Roch De Silva1, Lisette M Fred Lucena1
1Department of Chemistry, Georgetown University, Washington, DC 20057, USA.
Biomolecules
|December 23, 2022
Summary
Small molecule binding sites in intrinsically disordered proteins (IDPs) can be moved between proteins. Flanking residues influence binding, showing modularity but context-dependent affinity.
Area of Science:
- Biochemistry
- Molecular Biology
- Protein Science
Background:
- Intrinsically disordered proteins (IDPs) play crucial roles in cellular functions and disease.
- Targeting small molecules to IDPs is a promising therapeutic strategy, yet binding site mechanisms remain unclear.
Purpose of the Study:
- To investigate the portability and modularity of small-molecule binding sites within IDPs.
- To understand how flanking residues affect small-molecule binding affinity in different IDP contexts.
Main Methods:
- Identification of a minimal eight-residue binding sequence from the Myc protein.
- Reconstitution of this sequence into a different intrinsically disordered protein.
- Assessment of small-molecule binding activity and affinity in the new context.
Main Results:
- A minimal binding sequence from Myc retained small-molecule binding activity when transferred to another disordered protein.
- Residues adjacent to the minimal binding site modulated binding affinity differently depending on the protein context.
- Demonstrated modular and portable nature of IDP binding sites.
Conclusions:
- Small-molecule binding sites in IDPs can function as modular units transferable between disordered protein environments.
- Context-dependent modulation by flanking residues is critical for fine-tuning binding affinity.
- Findings advance the understanding of IDP-small molecule interactions and inform drug design strategies.
Keywords:
MycSLiMdrug targetsintrinsically disordered proteinsprotein-protein interactionsmall-molecule inhibitorsMore Related Videos
08:31Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
5.1K
08:49Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
458
Related Concept Videos
01:49Conserved Binding Sites
4.3K
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...
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...
4.3K
02:40Ligand Binding Sites
13.0K
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...
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...
13.0K
02:18Intrinsically Disordered Proteins
18.0K
Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
18.0K
00:49Ligand Binding and Linkage
4.9K
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...
4.9K
01:19Allosteric Proteins-ATCase
5.8K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.8K
01:58Cooperative Allosteric Transitions
8.0K
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...
8.0K