Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA(A) receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA(A) receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show that apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA(A) receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.
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PMID:A unitary anesthetic binding site at high resolution. 1960 49

Propofol (PFL, 1-hydroxyl-2,6-diisopropylbenzene) is currently used widely as one of the most well-known intravenous anesthetics to relieve surgical suffering, but its mechanism of action is not yet clear. Previous experimental studies have demonstrated that the hydroxyl group of PFL plays a dominant role in the molecular recognition of PFL with receptors that lead to hypnosis. To further explore the mechanism of anesthesia induced by PFL in the present work, the exact binding features and interaction details of PFL with three important proteins, human serum albumin (HSA), the pH-gated ion channel from Gloeobacter violaceus (GLIC), and horse spleen apoferritin (HSAF), were investigated systematically by using a rigorous three-layer ONIOM (M06-2X/6-31+G*:PM6:AMBER) method. Additionally, to further characterize the possible importance of such hydroxyl interactions, a similar set of calculations was carried out on the anesthetically inactive fropofol (FFL, 1-fluoro-2,6-diisopropylbenzene) in which the fluorine was substituted for the hydroxyl. According to the ONIOM calculations, atoms in molecules (AIM) analyses, and electrostatic potential (ESP) analyses, the significance of hydrogen bond, halogen bond, and hydrophobic interactions in promoting proper molecular recognition was revealed. The binding interaction energies of PFL with different proteins were generally larger than FFL and are a significant determinant of their differential anesthetic efficacies. Interestingly, although the hydrogen-bonding effect of the hydroxyl moiety was prominent in propofol, the substitution of the 1-hydroxyl by a fluorine atom did not prevent FFL from binding to the protein via a halogen-bonding interaction. It therefore became clear that multiple specific interactions rather than just hydrogen or halogen bonds must be taken into account to explain the different anesthesia endpoints caused by PFL and FFL. The contributions of key residues in ligand-receptor binding were also quantified, and the calculated results agreed with many available experimental observations. This work will provide complementary insights into the molecular mechanisms of anesthetic action for PFL from a robust theoretical point of view. This will not only assist in interpreting experimental observations but will also help to develop working hypotheses for further experiments and future drug design.
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PMID:The Role of the Hydroxyl Group in Propofol-Protein Target Recognition: Insights from ONIOM Studies. 2854 37