Daniel Nietlispach

Daniel Nietlispach

Integral membrane protein biology: structure, dynamics and function.

Lipid-embedded integral membrane proteins are highly abundant due to their relevance for cellular function. The Nietlispach Group is particularly interested in the family of seven-helical membrane proteins, and our current focus concentrates on G-protein-coupled receptors (GPCRs) and microbial rhodopsins. GPCRs are a group of around 850 proteins that relay diverse extracellular signal stimuli across the cell membrane, which activates signalling cascades resulting in cellular responses. GPCRs are involved in the regulation of many physiological processes and are the most important class of drug targets. While molecular insight on the structural features of these difficult-to-study proteins has dramatically increased over the years, it has become clear also that to function properly these proteins are very mobile. Therefore we are using NMR spectroscopy to characterise the dynamic nature of these receptors and investigate the mechanistic details of the signal activation process. NMR can equally report on molecular structure, binding events and conformational interchange taking place over a wide-range of timescales. Recently we have investigated the agonist-dependent conformational landscape of the β1-adrenergic receptor using a range of isotope labelling approaches.

Research objectives

  • How do the conformational dynamics of a membrane receptor relate to its function?

  • What are the mechanistic details of the signal transduction process involving GPCRs?

  • How is membrane protein function affected by environmental factors, for example lipids?

  • We are also interested in technical aspects: how can we improve the NMR methodology to enhance the study of biological systems?

Key publications

Frei JN, Broadhurst RW, Bostock MJ, Solt A, Jones AJY, Gabriel F, Tandale A, Shrestha B, Nietlispach D (2020). Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor. Nat. Commun., 11(1):669. doi: 10.1038/s41467-020-14526-3

Tan YL, Mitchell J, Klein-Seetharaman J, Nietlispach D (2019). Characterisation of denatured states of sensory rhodopsin II by solution-state NMR. J. Mol. Biol., 431(15):2790-2809. doi: 10.1016/j.jmb.2019.04.039

Solt AS, Bostock MJ, Shrestha B, Kumar P, Warne T, Tate CG, Nietlispach D (2017). Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound β1-adrenergic receptor. Nat. Commun., 8(1):1795. doi: 10.1038/s41467-017-02008-y

Chien CH, Helfinger LR, Bostock MJ, Solt A, Tan YL, Nietlispach D (2017). An adaptable phospholipid membrane mimetic system for solution NMR studies of membrane proteins. J. Am. Chem. Soc., 139(42):14829-14832. doi: 10.1021/jacs.7b06730

Bostock MJ, Holland DJ, Nietlispach D (2017). Improving resolution in multidimensional NMR using random quadrature detection with compressed sensing reconstruction. J. Biomol. NMR, 68(2):67-77. doi: 10.1007/s10858-016-0062-9