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Related Concept Videos

Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

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 pathway,...
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...
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...
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...
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...
Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

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Updated: Jun 27, 2026

Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach

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Allosteric P450 mechanisms: multiple binding sites, multiple conformers or both?

Dmitri R Davydov1, James R Halpert

  • 1Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, 9500 Gilman Drive, La Jolla, CA 9209, USA. ddavydov@ucsd.edu

Expert Opinion on Drug Metabolism & Toxicology
|December 2, 2008
PubMed
Summary
This summary is machine-generated.

Cooperativity in drug-metabolizing cytochromes P450 (CYP450) involves multiple ligand binding and ligand-induced conformational changes. This study explains complex CYP450 kinetics using an oligomeric allosteric enzyme model.

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Structure-Guided Design and Development of Novel Cyclophilin A Inhibitors and Ganoderiol-F Derivatives: An In-Silico Approach
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Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Cytochromes P450 (CYP450) are crucial for drug metabolism.
  • Initial hypotheses suggested cooperativity in CYP450 arises from multiple ligand binding.
  • Atypical kinetic behaviors in CYP450 have been observed.

Purpose of the Study:

  • To explore the mechanistic basis of cooperativity in drug-metabolizing cytochromes P450.
  • To investigate the role of ligand-induced conformational transitions in CYP450 function.
  • To explain complex kinetic behaviors of CYP450 enzymes.

Main Methods:

  • Review of existing literature on CYP450 cooperativity.
  • Analysis of simultaneous multiple ligand occupancy in CYP450 active sites.
  • Application of the oligomeric allosteric enzyme concept to CYP450.

Main Results:

  • Evidence supports ligand-induced conformational transitions as a key mechanism for cooperativity.
  • Ligand-dependent interactions stabilize conformational heterogeneity among CYP450 molecules.
  • The oligomeric allosteric enzyme model effectively explains complex CYP450 kinetics.

Conclusions:

  • Cooperativity in CYP450 is a complex phenomenon involving both multiple ligand occupancy and conformational changes.
  • Ligand interactions stabilize enzyme conformation, influencing catalytic activity.
  • An allosteric enzyme framework provides a comprehensive explanation for CYP450 kinetic behavior.