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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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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...
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Allosteric Proteins-ATCase01:19

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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...
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Ligand Binding and Linkage00:49

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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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Conserved Binding Sites01:49

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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.
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Protein-protein Interfaces02:04

Protein-protein Interfaces

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Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
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Ligand Binding Sites02:40

Ligand Binding Sites

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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.
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Related Experiment Video

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Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
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Predicting binding events in very flexible, allosteric, multi-domain proteins.

Andrea Basciu1, Mohd Athar1, Han Kurt1

  • 1Physics Department, University of Cagliari, Cittadella Universitaria, I-09042 Monserrato (CA), Italy.

Biorxiv : the Preprint Server for Biology
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Summary

This study introduces a novel method to predict protein-ligand interactions, even for flexible proteins, improving drug discovery. The approach accurately models complex binding events, enhancing virtual screening for new therapeutics.

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Related Experiment Videos

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A Protocol for Computer-Based Protein Structure and Function Prediction
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A Protocol for Computer-Based Protein Structure and Function Prediction

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Understanding protein-small molecule interactions is crucial for chemotherapy and drug design.
  • Current in silico methods struggle with large conformational changes in flexible proteins during virtual screening.
  • Allosteric proteins with multiple binding sites present significant challenges for predicting ligand-protein complexes.

Purpose of the Study:

  • To develop a new methodology for generating bound-like protein conformations from unbound structures.
  • To address limitations in predicting binding events involving large protein conformational changes.
  • To create a versatile framework for modeling diverse ligand interactions with challenging drug targets.

Main Methods:

  • A novel protocol utilizing unbound protein structures and putative binding site information.
  • Generation of bound-like conformations for flexible and allosteric proteins.
  • Validation using ensemble-docking calculations on the adenylate kinase enzyme.

Main Results:

  • Successfully generated a significant fraction of bound-like conformations for adenylate kinase.
  • Identified native-like poses for substrates and inhibitors using ensemble-docking.
  • Differentiated binding poses for active and inactive enzyme forms, including catalytically incompetent analogs.

Conclusions:

  • The developed protocol effectively generates bound-like conformations for challenging drug targets.
  • The method demonstrates sensitivity to chemical details influencing protein activity.
  • Applications include enhanced virtual screening, mutation impact prediction, and protein engineering.