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Dr Daniel Nietlispach

Abstract:

Investigating the dynamic nature of GPCR signaling by NMR spectroscopy    G protein-coupled receptors (GPCRs) constitute the largest family of integral membrane proteins that regulate most aspects of normal physiology. From a mechanistic perspective but also for human health, understanding how GPCRs work remains one of the most important and challenging questions in biology. The current understanding of GPCR activation derives in large part from crystal structure information of inactive and active receptor states. However, GPCRs are highly dynamic molecules and downstream signaling events follow from extracellular ligand-induced interactions that dynamically change the functional state of the receptor. Insight into this functional receptor plasticity is not accessible through crystal structures and a snapshot representation of the receptor is not sufficient to reveal all essential aspects of GPCR function. Complementary studies are required therefore that provide information on receptor dynamics. Our group uses a solution NMR spectroscopy approach to obtain information on molecular dynamics, structure and ligand binding of these receptors. The current work will involve the development of selective isotope labeling strategies optimized for solution NMR spectroscopy in order to probe the conformational sampling of the b1AR receptor while embedded in a range of membrane mimetics.

References:

  1. Gautier, A., Kirkpatrick, J.P. and Nietlispach, D. (2008) Solution-state NMR spectroscopy of a seven-helix transmembrane protein receptor: Backbone assignment, secondary structure, and dynamics. Angew. Chem.-Int. Edit. 47, 7297-7300.    
  2. Gautier, A., Mott, H.R., Bostock, M.J., Kirkpatrick, J.P. and Nietlispach, D. (2010) Structure determination of the seven-helix transmembrane receptor sensory rhodopsin II by solution NMR spectroscopy. Nat. Struct. Mol. Biol. 17, 768-774.  
  3. Holland, D.J., Bostock, M.J., Gladden, L.F. and Nietlispach, D. (2011) Fast Multidimensional NMR Spectroscopy Using Compressed Sensing. Angew. Chem.-Int. Edit. 50, 6548-6551.

Dr Daniel Nietlispach

Dr Daniel Nietlispach
Department of Biochemistry
Office Phone: 01223 366023