A Unitary Anesthetic Binding Site at High Resolution

Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABAA 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 GABAA 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 GABAA 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. Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABAA 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 GABAA 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 GABAA 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. Most general anesthetics alter the activity of ligand-gated ion channels, and electrophysiology, photolabeling, and transgenic animal experiments imply that this effect contributes to the mechanism of anesthesia (1.Mascia M.P. Trudell J.R. Harris R.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 9305-9310Crossref PubMed Scopus (232) Google Scholar, 2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 3.Krasowski M.D. Nishikawa K. Nikolaeva N. Lin A. Harrison N.L. Neuropharmacology. 2001; 41: 952-964Crossref PubMed Scopus (111) Google Scholar, 4.Jenkins A. Andreasen A. Trudell J.R. Harrison N.L. Neuropharmacology. 2002; 43: 669-678Crossref PubMed Scopus (57) Google Scholar, 5.Siegwart R. Jurd R. Rudolph U. J. Neurochem. 2002; 80: 140-148Crossref PubMed Scopus (119) Google Scholar, 6.Chang C.S. Olcese R. Olsen R.W. J. Biol. Chem. 2003; 278: 42821-42828Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Jurd R. Arras M. Lambert S. Drexler B. Siegwart R. Crestani F. Zaugg M. Vogt K.E. Ledermann B. Antkowiak B. Rudolph U. FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (498) Google Scholar, 8.Schofield C.M. Harrison N.L. Brain Res. 2005; 1032: 30-35Crossref PubMed Scopus (20) Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google Scholar). Although the molecular mechanism for this effect is not yet clear, photolabeling studies indicate that anesthetics bind within the transmembrane regions of Cys-loop ligand-gated ion channels such as the nicotinic acetylcholine and the γ-aminobutyric acid (GABA) 2The abbreviations used are: GABAγ-aminobutyric acidHSAhuman serum albuminHSAFhorse spleen apoferritinITCisothermal calorimetryLGICligand-gated ion channelr.m.s.root mean squareRMSFroot mean squared fluctuations. 2The abbreviations used are: GABAγ-aminobutyric acidHSAhuman serum albuminHSAFhorse spleen apoferritinITCisothermal calorimetryLGICligand-gated ion channelr.m.s.root mean squareRMSFroot mean squared fluctuations. type A receptors (2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google Scholar, 10.Chiara D. Dangott L.J. Eckenhoff R.G. Cohen J.B. Biochemistry. 2003; 42: 13457-13467Crossref PubMed Scopus (91) Google Scholar, 11.Miyazawa A. Fujiyoshi Y. Unwin N. Nature. 2003; PubMed Scopus Google Scholar). with and of ion channels have of the structural and anesthetic recognition. general anesthetics also bind to in serum and spleen apoferritin Nature. PubMed Scopus Google Scholar, R. J. J. Eckenhoff R.G. J. PubMed Scopus Google Scholar, R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google and x-ray crystal structures have for complexes of with general anesthetics R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google Scholar, A. E. J. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is model for it the for anesthetics of protein to a anesthetic binding and is a of like the anesthetic binding regions in ligand-gated channels. apoferritin is and Most the of for a of general anesthetics is correlated with anesthetic the and of this model system J. R.A. Eckenhoff R.G. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google is a to of in the and as a A. R. K. of Scholar, D. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a molecular of and a a with found in and and of the of the is not yet S. and Google to the the apoferritin at the of to anesthetics. that this is the binding site for the inhalational anesthetics and and have shown that this site a for anesthetics R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google anesthetics at inhalational and both of the and with in the in their and to this crystal for injectable general anesthetic with a to S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that the propofol binding this protein by and with the binding for inhalational anesthetics. the of the of bind to of their by binding to a protein this we propofol binds to the apoferritin site that previously as the binding site for inhalational anesthetics. x-ray and molecular we show that the of anesthetics a binding We also for a series of and found that, the of binding to apoferritin the to potentiate GABA at GABAA receptors, that structural and anesthetic recognition by both apoferritin and ligand-gated ion channels. for the that anesthetic binding structural and dynamic in GABAA receptors to in and that changes anesthetic is the most widely used of the injectable general anesthetics. of and of the with such as and Y. M. S. Neurosci. PubMed Scopus Google Scholar). Its to of GABAergic have for propofol analogs M.D. A. Harrison N.L. J. 2001; Google but the atomic details of the necessary to have not such details for the protein we a series of that the same but in the of the at the and apoferritin system a in which not for recognition of propofol and related of the in with the within the apoferritin and despite the that of the of in hydrogen and their molecular dynamics simulations show that the ligands to hydrogen to in the to their protein is that hydrogen not in propofol that the of the propofol J. Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. Harrison N.L. J. Chem. 2002; PubMed Scopus Google Scholar). strongly that the may to to protein the of such as hydrogen be by van der Waals forces and of the and We the the effect a of of hydrophobic Proc. Natl. Acad. Sci. U.S.A. PubMed Google and found with that the hydrophobic effect is the anesthetic recognition by apoferritin the ligands the this with a binding that is by the hydrophobic effect. the of a in the of and is with the molecular dynamics which that ligands a considerable of within the the recognition of by which is also by forces S. J. Chem. J. Scopus Google and that to a of within the of about to the of most to and and for complexes to with binding at a of and for that apoferritin include to the and in with the of the model S. J. Chem. J. Scopus Google ligands with in of this of this in we the and binding of propofol for R. J. J. Eckenhoff R.G. J. PubMed Scopus Google Scholar, S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Propofol binds in of for the R. J. J. Eckenhoff R.G. J. PubMed Scopus Google which is more the apoferritin for of the is a and S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in the is the found for the that the for propofol may in a binding of complexes that this is of the that it the that it in the complex may that the a hydrogen bond propofol and for the of the of both the and the dynamics of the apoferritin model reveal a complex anesthetic and crystal structures show that the protein is able to at to a to ligands that anesthetics bind to may be molecular dynamics simulations this structural for the for the that the at a it is not to that of in the transmembrane regions of ion channels the of of structural with dynamics simulations is by the of anesthetic binding and for the not and molecular dynamics simulations reveal that the of anesthetic binding protein at the binding site the and is to by anesthetic binding to apoferritin is to as a model system in ability to relevant anesthetic for propofol and related reveal a anesthetic by of in and the ability to potentiate GABA responses at GABAA receptors M.D. A. Harrison N.L. J. 2001; Google a GABAergic mechanism for is to that in the propofol binding for apoferritin is strongly correlated with of GABA responses this the of that of site in the GABAA complex is for A is also apoferritin binding and anesthetic in not as as with GABA is not that systems responses such as the of apoferritin binding and the for of GABA responses at GABAA receptors by and is as the GABA M.D. A. Harrison N.L. J. 2001; Google Scholar). shown to and a to the a of within the for the of the the that apoferritin as a model for the GABAA is with of and photolabeling experiments (1.Mascia M.P. Trudell J.R. Harris R.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 9305-9310Crossref PubMed Scopus (232) Google Scholar, 2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 3.Krasowski M.D. Nishikawa K. Nikolaeva N. Lin A. Harrison N.L. Neuropharmacology. 2001; 41: 952-964Crossref PubMed Scopus (111) Google Scholar, 4.Jenkins A. Andreasen A. Trudell J.R. Harrison N.L. Neuropharmacology. 2002; 43: 669-678Crossref PubMed Scopus (57) Google Scholar, 5.Siegwart R. Jurd R. Rudolph U. J. Neurochem. 2002; 80: 140-148Crossref PubMed Scopus (119) Google Scholar, 6.Chang C.S. Olcese R. Olsen R.W. J. Biol. Chem. 2003; 278: 42821-42828Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Jurd R. Arras M. Lambert S. Drexler B. Siegwart R. Crestani F. Zaugg M. Vogt K.E. Ledermann B. Antkowiak B. Rudolph U. FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (498) Google Scholar, 8.Schofield C.M. Harrison N.L. Brain Res. 2005; 1032: 30-35Crossref PubMed Scopus (20) Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google with G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google have that the anesthetic binding site of the GABAA within transmembrane at the the apoferritin anesthetic binding site is found in the structural to the atomic is apoferritin and the GABAA receptor, is the found in apoferritin with we of the of the transmembrane of ligand-gated ion channels. apoferritin displays a of at the and structural apoferritin binding anesthetic in a of van der Waals forces and the hydrophobic at the same binding site previously shown to bind inhalational general anesthetics such as and with the structural strongly that the apoferritin anesthetic binding site a of and to that in the GABAA and clinically relevant will the of structural and to anesthetic within relevant ion Most general anesthetics alter the activity of ligand-gated ion channels, and electrophysiology, photolabeling, and transgenic animal experiments imply that this effect contributes to the mechanism of anesthesia (1.Mascia M.P. Trudell J.R. Harris R.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 9305-9310Crossref PubMed Scopus (232) Google Scholar, 2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 3.Krasowski M.D. Nishikawa K. Nikolaeva N. Lin A. Harrison N.L. Neuropharmacology. 2001; 41: 952-964Crossref PubMed Scopus (111) Google Scholar, 4.Jenkins A. Andreasen A. Trudell J.R. Harrison N.L. Neuropharmacology. 2002; 43: 669-678Crossref PubMed Scopus (57) Google Scholar, 5.Siegwart R. Jurd R. Rudolph U. J. Neurochem. 2002; 80: 140-148Crossref PubMed Scopus (119) Google Scholar, 6.Chang C.S. Olcese R. Olsen R.W. J. Biol. Chem. 2003; 278: 42821-42828Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Jurd R. Arras M. Lambert S. Drexler B. Siegwart R. Crestani F. Zaugg M. Vogt K.E. Ledermann B. Antkowiak B. Rudolph U. FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (498) Google Scholar, 8.Schofield C.M. Harrison N.L. Brain Res. 2005; 1032: 30-35Crossref PubMed Scopus (20) Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google Scholar). Although the molecular mechanism for this effect is not yet clear, photolabeling studies indicate that anesthetics bind within the transmembrane regions of Cys-loop ligand-gated ion channels such as the nicotinic acetylcholine and the γ-aminobutyric acid (GABA) 2The abbreviations used are: GABAγ-aminobutyric acidHSAhuman serum albuminHSAFhorse spleen apoferritinITCisothermal calorimetryLGICligand-gated ion channelr.m.s.root mean squareRMSFroot mean squared fluctuations. 2The abbreviations used are: GABAγ-aminobutyric acidHSAhuman serum albuminHSAFhorse spleen apoferritinITCisothermal calorimetryLGICligand-gated ion channelr.m.s.root mean squareRMSFroot mean squared fluctuations. type A receptors (2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google Scholar, 10.Chiara D. Dangott L.J. Eckenhoff R.G. Cohen J.B. Biochemistry. 2003; 42: 13457-13467Crossref PubMed Scopus (91) Google Scholar, 11.Miyazawa A. Fujiyoshi Y. Unwin N. Nature. 2003; PubMed Scopus Google Scholar). with and of ion channels have of the structural and anesthetic recognition. general anesthetics also bind to in serum and spleen apoferritin Nature. PubMed Scopus Google Scholar, R. J. J. Eckenhoff R.G. J. PubMed Scopus Google Scholar, R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google and x-ray crystal structures have for complexes of with general anesthetics R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google Scholar, A. E. J. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is model for it the for anesthetics of protein to a anesthetic binding and is a of like the anesthetic binding regions in ligand-gated channels. apoferritin is and Most the of for a of general anesthetics is correlated with anesthetic the and of this model system J. R.A. Eckenhoff R.G. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). γ-aminobutyric acid serum spleen apoferritin ligand-gated ion mean mean squared fluctuations. γ-aminobutyric acid serum spleen apoferritin ligand-gated ion mean mean squared fluctuations. is a to of in the and as a A. R. K. of Scholar, D. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a molecular of and a a with found in and and of the of the is not yet S. and Google Scholar). to the the apoferritin at the of to anesthetics. that this is the binding site for the inhalational anesthetics and and have shown that this site a for anesthetics R. Eckenhoff R.G. FASEB J. 2005; PubMed Scopus Google Scholar). anesthetics at inhalational and both of the and with in the in their and to this crystal for injectable general anesthetic with a to S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that the propofol binding this protein by and with the binding for inhalational anesthetics. the of the of bind to of their by binding to a protein this we propofol binds to the apoferritin site that previously as the binding site for inhalational anesthetics. x-ray and molecular we show that the of anesthetics a binding We also for a series of and found that, the of binding to apoferritin the to potentiate GABA at GABAA receptors, that structural and anesthetic recognition by both apoferritin and ligand-gated ion channels. for the that anesthetic binding structural and dynamic in GABAA receptors to in and that changes anesthetic is the most widely used of the injectable general anesthetics. of and of the with such as and Y. M. S. Neurosci. PubMed Scopus Google Scholar). Its to of GABAergic have for propofol analogs M.D. A. Harrison N.L. J. 2001; Google but the atomic details of the necessary to have not such details for the protein we a series of that the same but in the of the at the and apoferritin system a in which not for recognition of propofol and related of the in with the within the apoferritin and despite the that of the of in hydrogen and their molecular dynamics simulations show that the ligands to hydrogen to in the to their protein is that hydrogen not in propofol that the of the propofol J. Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. Harrison N.L. J. Chem. 2002; PubMed Scopus Google Scholar). strongly that the may to to protein the of such as hydrogen be by van der Waals forces and of the and We the the effect a of of hydrophobic Proc. Natl. Acad. Sci. U.S.A. PubMed Google and found with that the hydrophobic effect is the anesthetic recognition by apoferritin the ligands the this with a binding that is by the hydrophobic effect. the of a in the of and is with the molecular dynamics which that ligands a considerable of within the the recognition of by which is also by forces S. J. Chem. J. Scopus Google and that to a of within the of about to the of most to and and for complexes to with binding at a of and for that apoferritin include to the and in with the of the model S. J. Chem. J. Scopus Google ligands with in of this of this in we the and binding of propofol for R. J. J. Eckenhoff R.G. J. PubMed Scopus Google Scholar, S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Propofol binds in of for the R. J. J. Eckenhoff R.G. J. PubMed Scopus Google which is more the apoferritin for of the is a and S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in the is the found for the that the for propofol may in a binding of complexes that this is of the that it the that it in the complex may that the a hydrogen bond propofol and for the of the of both the and the dynamics of the apoferritin model reveal a complex anesthetic and crystal structures show that the protein is able to at to a to ligands that anesthetics bind to may be molecular dynamics simulations this structural for the for the that the at a it is not to that of in the transmembrane regions of ion channels the of of structural with dynamics simulations is by the of anesthetic binding and for the not and molecular dynamics simulations reveal that the of anesthetic binding protein at the binding site the and is to by anesthetic binding to apoferritin is to as a model system in ability to relevant anesthetic for propofol and related reveal a anesthetic by of in and the ability to potentiate GABA responses at GABAA receptors M.D. A. Harrison N.L. J. 2001; Google a GABAergic mechanism for is to that in the propofol binding for apoferritin is strongly correlated with of GABA responses this the of that of site in the GABAA complex is for A is also apoferritin binding and anesthetic in not as as with GABA is not that systems responses such as the of the that apoferritin as a model for the GABAA is with of and photolabeling experiments (1.Mascia M.P. Trudell J.R. Harris R.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 9305-9310Crossref PubMed Scopus (232) Google Scholar, 2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 3.Krasowski M.D. Nishikawa K. Nikolaeva N. Lin A. Harrison N.L. Neuropharmacology. 2001; 41: 952-964Crossref PubMed Scopus (111) Google Scholar, 4.Jenkins A. Andreasen A. Trudell J.R. Harrison N.L. Neuropharmacology. 2002; 43: 669-678Crossref PubMed Scopus (57) Google Scholar, 5.Siegwart R. Jurd R. Rudolph U. J. Neurochem. 2002; 80: 140-148Crossref PubMed Scopus (119) Google Scholar, 6.Chang C.S. Olcese R. Olsen R.W. J. Biol. Chem. 2003; 278: 42821-42828Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Jurd R. Arras M. Lambert S. Drexler B. Siegwart R. Crestani F. Zaugg M. Vogt K.E. Ledermann B. Antkowiak B. Rudolph U. FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (498) Google Scholar, 8.Schofield C.M. Harrison N.L. Brain Res. 2005; 1032: 30-35Crossref PubMed Scopus (20) Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google with G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google have that the anesthetic binding site of the GABAA within transmembrane at the the apoferritin anesthetic binding site is found in the structural to the atomic is apoferritin and the GABAA receptor, is the found in apoferritin with we of the of the transmembrane of ligand-gated ion channels. apoferritin displays a of at the and structural apoferritin binding anesthetic in a of van der Waals forces and the hydrophobic at the same binding site previously shown to bind inhalational general anesthetics such as and with the structural strongly that the apoferritin anesthetic binding site a of and to that in the GABAA and clinically relevant will the of structural and to anesthetic within relevant ion Propofol is the most widely used of the injectable general anesthetics. of and of the with such as and Y. M. S. Neurosci. PubMed Scopus Google Scholar). Its to of GABAergic have for propofol analogs M.D. A. Harrison N.L. J. 2001; Google but the atomic details of the necessary to have not such details for the protein we a series of that the same but in the of the at the and apoferritin system a in which not for recognition of propofol and related of the in with the within the apoferritin and despite the that of the of in hydrogen and their molecular dynamics simulations show that the ligands to hydrogen to in the to their protein is that hydrogen not in propofol that the of the propofol J. Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. Harrison N.L. J. Chem. 2002; PubMed Scopus Google Scholar). strongly that the may to to protein recognition. the of such as hydrogen be by van der Waals forces and of the and We the the effect a of of hydrophobic Proc. Natl. Acad. Sci. U.S.A. PubMed Google and found with that the hydrophobic effect is the anesthetic recognition by apoferritin the ligands the this with a binding that is by the hydrophobic effect. the of a in the of and is with the molecular dynamics which that ligands a considerable of within the A the recognition of by which is also by forces S. J. Chem. J. Scopus Google and that to a of within the of about to the of most to and and for complexes to with binding at a of and for that apoferritin include to the and in with the of the model S. J. Chem. J. Scopus Google ligands with in of this of this in we the and binding of propofol for R. J. J. Eckenhoff R.G. J. PubMed Scopus Google Scholar, S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Propofol binds in of for the R. J. J. Eckenhoff R.G. J. PubMed Scopus Google which is more the apoferritin for of the is a and S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in the is the found for the that the for propofol may in a binding of complexes that this is of the that it the that it in the complex may that the a hydrogen bond propofol and for the of the of both the and the dynamics of the apoferritin model reveal a complex anesthetic and crystal structures show that the protein is able to at to a to ligands that anesthetics bind to may be molecular dynamics simulations this structural for the for the that the at a it is not to that of in the transmembrane regions of ion channels the of of structural with dynamics simulations is by the of anesthetic binding and for the not and molecular dynamics simulations reveal that the of anesthetic binding protein at the binding site the and is to by anesthetic binding to apoferritin is to as a model system in ability to relevant anesthetic for propofol and related reveal a anesthetic by of in and the ability to potentiate GABA responses at GABAA receptors M.D. A. Harrison N.L. J. 2001; Google a GABAergic mechanism for is to that in the propofol binding for apoferritin is strongly correlated with of GABA responses this the of that of site in the GABAA complex is for A is also apoferritin binding and anesthetic in not as as with GABA is not that systems responses such as the of the that apoferritin as a model for the GABAA is with of and photolabeling experiments (1.Mascia M.P. Trudell J.R. Harris R.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 9305-9310Crossref PubMed Scopus (232) Google Scholar, 2.Jenkins A. Greenblatt E.P. Faulkner H.J. Bertaccini E. Light A. Lin A. Andreasen A. Viner A. Trudell J.R. Harrison N.L. J. Neurosci. 2001; 21: RC136Crossref PubMed Google Scholar, 3.Krasowski M.D. Nishikawa K. Nikolaeva N. Lin A. Harrison N.L. Neuropharmacology. 2001; 41: 952-964Crossref PubMed Scopus (111) Google Scholar, 4.Jenkins A. Andreasen A. Trudell J.R. Harrison N.L. Neuropharmacology. 2002; 43: 669-678Crossref PubMed Scopus (57) Google Scholar, 5.Siegwart R. Jurd R. Rudolph U. J. Neurochem. 2002; 80: 140-148Crossref PubMed Scopus (119) Google Scholar, 6.Chang C.S. Olcese R. Olsen R.W. J. Biol. Chem. 2003; 278: 42821-42828Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Jurd R. Arras M. Lambert S. Drexler B. Siegwart R. Crestani F. Zaugg M. Vogt K.E. Ledermann B. Antkowiak B. Rudolph U. FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (498) Google Scholar, 8.Schofield C.M. Harrison N.L. Brain Res. 2005; 1032: 30-35Crossref PubMed Scopus (20) Google Scholar, 9.Li G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google with G.D. Chiara D.C. Sawyer G.W. Husain S.S. Olsen R.W. Cohen J.B. J. Neurosci. 2006; 26: 11599-11605Crossref PubMed Scopus (248) Google have that the anesthetic binding site of the GABAA within transmembrane at the the apoferritin anesthetic binding site is found in the structural to the atomic is apoferritin and the GABAA receptor, is the found in apoferritin with we of the of the transmembrane of ligand-gated ion channels. apoferritin displays a of at the and structural apoferritin binding anesthetic in a of van der Waals forces and the hydrophobic at the same binding site previously shown to bind inhalational general anesthetics such as and with the structural strongly that the apoferritin anesthetic binding site a of and to that in the GABAA and clinically relevant will the of structural and to anesthetic within relevant ion We and for to for this study were at and of the Light and the of the at for the the of and and of of the of and the for of the of of the at the is by the of the a with the for at the of with with