Nicotinic Acetylcholine Receptor Structure, Thermal Motion and Gating

Summary

Principal Investigator: Michaela Jansen
Abstract: This research project aims at studying the muscle nicotinic acetylcholine receptor (nAChR) structure and the conformational changes it undergoes during channel activation. Nicotinic AChR mediate fast synaptic transmission at the nerve-muscle junction and in the brain. The recent publication of the ACh binding protein (AChBP) and Torpedo AChR structures has allowed new insights into the three dimensional structure and provides the basis for the following Specific Aims: 1) To test the validity of the 4-A resolution AChR transmembrane domain model by determining proximity relationships between specific transmembrane segment residues. 2) To determine the thermal mobility of the M2 channel-lining segments in the resting and activated states. 3) To map structural changes in the transmembrane domain during activation. 4) To probe protein packing around the M2-M3 loop that is involved in the transduction of ligand binding to channel gating. The results will validate the structural information inferred from the 4-A resolution data. In addition they will be used to refine the structural model of the receptor. This will allow more detailed investigations of binding sites for allosteric ligands, thus allowing design of Improved drugs, in addition, this study will elucidate dynamic events such as thermal and gating-induced movements.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Structural sensitivity of a prokaryotic pentameric ligand-gated ion channel to its membrane environment
    Jonathan M Labriola
    Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
    J Biol Chem 288:11294-303. 2013
  2. pmc Experimental determination of the vertical alignment between the second and third transmembrane segments of muscle nicotinic acetylcholine receptors
    Nelli Mnatsakanyan
    Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
    J Neurochem 125:843-54. 2013
  3. pmc Probing protein packing surrounding the residues in and flanking the nicotinic acetylcholine receptor M2M3 loop
    Roger Ernest Wiltfong
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 29:1626-35. 2009
  4. pmc GABA-induced intersubunit conformational movement in the GABAA receptor alpha 1M1-beta 2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site
    Moez Bali
    Department of Physiology and Biophysics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA
    J Neurosci 29:3083-92. 2009
  5. pmc Engineering a prokaryotic Cys-loop receptor with a third functional domain
    Raman Goyal
    Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
    J Biol Chem 286:34635-42. 2011

Detail Information

Publications5

  1. pmc Structural sensitivity of a prokaryotic pentameric ligand-gated ion channel to its membrane environment
    Jonathan M Labriola
    Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
    J Biol Chem 288:11294-303. 2013
    ..Structural comparisons provide insight into the chemical features that may predispose the nAChR to the formation of an uncoupled state...
  2. pmc Experimental determination of the vertical alignment between the second and third transmembrane segments of muscle nicotinic acetylcholine receptors
    Nelli Mnatsakanyan
    Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
    J Neurochem 125:843-54. 2013
    ..Our results further confirm that this alignment in Cys-loop receptors is conserved between prokaryotes and eukaryotes...
  3. pmc Probing protein packing surrounding the residues in and flanking the nicotinic acetylcholine receptor M2M3 loop
    Roger Ernest Wiltfong
    Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 29:1626-35. 2009
    ..Our data indicate that the Torpedo nAChR transmembrane domain structure is a better model than the ELIC structure for eukaryotic Cys-loop receptors...
  4. pmc GABA-induced intersubunit conformational movement in the GABAA receptor alpha 1M1-beta 2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site
    Moez Bali
    Department of Physiology and Biophysics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA
    J Neurosci 29:3083-92. 2009
    ..This supports the hypothesis that some intravenous anesthetics bind in the betaM3-alphaM1 subunit interface consistent with azi-etomidate photoaffinity labeling...
  5. pmc Engineering a prokaryotic Cys-loop receptor with a third functional domain
    Raman Goyal
    Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA
    J Biol Chem 286:34635-42. 2011
    ..Our results indicate that the ICD can be considered a separate domain that can be removed from or added to the ECD and TMD while maintaining the overall structure and function of the ECD and TMD...