Project A02 – Investigation of the structure and dynamics of the ghrelin/GHS receptor complex

The peptide hormone ghrelin plays a key role in food uptake and the regulation of body mass. Ghrelin binds and activates the GHS receptor. In the project, structural details of the dynamic interaction of ghrelin with its receptor will be studied. We will use a combination of experimental methods of magnetic resonance spectroscopy and computer simulation tools. In particular, we will describe structural changes on the GHS receptor that occur upon binding of the agonist ghrelin and address the mechanism of recognition. We will pay special attention to the covalently attached lipid modification of ghrelin, a molecular specificity which is unique among all hormones in the human body. The long-term goal of this work is the development of a structural model of the complex of receptor and ligand.

Contact

Prof. Dr. Daniel Huster (Project Leader)

Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, 04107 Leipzig

Phone +49 341 97 15701
E-Mail
Web biophysik.medizin.uni-leipzig.de

Prof. Dr. Peter Hildebrand (Project Leader)

Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, 04107 Leipzig

Phone +49 341 97 15705
E-Mail
Web biophysik.medizin.uni-leipzig.de/forschungresearch/prof-dr-peter-hildebrand/

Resources

Structural dynamics of G-protein coupled receptors (GPCRs)

  1. Mechanism, specificity and dynamics of receptor-mediated signal transduction to G-proteins and arrestins using different molecular dynamics methods
  2. Development of web applications for the analysis and visualization of simulation trajectories, for example receptor activation and G-protein or arrestin binding
  • Bruker Avance III 600 MHz NMR spectrometer
  • Bruker Avance I 700 MHz NMR spectrometer
  • Linux GPU HPC-Cluster for MDSimulations
  • New Avance Neo Console for 700 MHz NMR spectrometer and 2 solids probes

Publications

Krug U, Gloge A, Schmidt P, Becker-Baldus J, Bernhard F, Kaiser A, Montag C, Gauglitz M, Vishnivetskiy SA, Gurevich VVBeck-Sickinger AG, Glaubitz C, Huster D. The Conformational Equilibrium of the Neuropeptide Y2 Receptor in Bilayer Membranes. Angew Chem Int Ed Engl. 2020 Aug 13. doi: 10.1002/anie.202006075. Epub ahead of print. PMID: 32790043

Liu X, Xu X, Hilger D, Aschauer P, Tiemann JKS, Du Y, Liu H, Hirata K, Sun X, Guixà-González R, Mathiesen JM, Hildebrand PW, Kobilka BK. Structural Insights into the Process of GPCR-G Protein Complex Formation. Cell. 2019 May 16;177(5):1243-1251.e12. doi: 10.1016/j.cell.2019.04.021 Epub 2019 May 9. PMID: 31080070 PMCID: PMC6991123 

Ma X, Hu Y, Batebi H, Heng J, Xu J, Liu X, Niu X, Li H, Hildebrand PW, Jin C, Kobilka BK. Analysis of β2AR-Gs and β2AR-Gi complex formation by NMR spectroscopy. Proc Natl Acad Sci U S A. 2020 Aug 31:202009786. doi: 10.1073/pnas.2009786117. Epub ahead of print. PMID: 32868434

Mayol E, García-Recio A, Tiemann JKS, Hildebrand PW, Guixà-González R, Olivella M, Cordomí A. HomolWat: a web server tool to incorporate ‘homologous’ water molecules into GPCR structures. Nucleic Acids Res. 2020 Jul 2;48(W1):W54-W59. doi: 10.1093/nar/gkaa440. PMID: 32484557; PMCID: PMC7319549

Rodríguez-Espigares I, Torrens-Fontanals M, Tiemann JKS, Aranda-García D, Ramírez-Anguita JM, Stepniewski TM, Worp N, Varela-Rial A, Morales-Pastor A, Medel-Lacruz B, Pándy-Szekeres G, Mayol E, Giorgino T, Carlsson J, Deupi X, Filipek S, Filizola M, Gómez-Tamayo JC, Gonzalez A, Gutiérrez-de-Terán H, Jiménez-Rosés M, Jespers W, Kapla J, Khelashvili G, Kolb P, Latek D, Marti-Solano M, Matricon P, Matsoukas MT, Miszta P, Olivella M, Perez-Benito L, Provasi D, Ríos S, R Torrecillas I, Sallander J, Sztyler A, Vasile S, Weinstein H, Zachariae U, Hildebrand PW, De Fabritiis G, Sanz F, Gloriam DE, Cordomi A, Guixà-González R, Selent J. GPCRmd uncovers the dynamics of the 3D-GPCRome. Nat Methods. 2020 Jul 13. doi: 10.1038/s41592-020-0884-y. Epub ahead of print. Erratum in: Nat Methods. 2020 Jul 23;: PMID: 32661425

Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B. Structural basis of ligand binding modes of neuropeptide Y Y1 receptor. Nature. 2018; 556:520-4.

Saleh N, Hucke O, Kramer G, Schmidt E, Montel F, Lipinski R, Ferger B, Clark T, Hildebrand PW, Tautermann CS. Multiple binding sites contribute to the mechanism of mixed agonistic and positive allosteric modulators of the cannabinoid CB1 receptor. Angew Chem Int Ed. 2018; 57:2580-5.

Saleh N, Kleinau G, Heyder N, Clark T, Hildebrand PW, Scheerer P. Binding, thermodynamics and selectivity of a non-peptide antagonist to the Melanocortin-4 receptor. Frontiers Pharmakol. 2018; 9:560.

Guixà-González R, Albasanz JL, Rodriguez-Espigares I, Pastor M, Sanz F, Martí-Solano M, Moutusi Manna, Hildebrand PW, Martinez-Seara H, Martín M, Selent J. Access of membrane cholesterol to a G protein coupled receptor. Nat Comm. 2017; 8:14505.

Schrottke S, Vortmeier G, Els-Heindl S, Bosse M, Schmidt P, Scheidt HA, Beck-Sickinger AG, Huster D. Expression, functional characterization, and solid-state NMR investigation of the G protein-coupled GHS receptor in bilayer membranes. Sci Rep. 2017; 7:46128.

Kaiser A, Müller P, Zellmann T, Scheidt HA, Bosse M, Meier R, Meiler J, Huster D, Beck-Sickinger AG, Schmidt P. NMR-guided structural model of neuropeptide Y Bound to its G protein-coupled Y2Angew Chem Int Ed. 2015; 52:7446-9.

Vortmeier G. DeLuca SH, Els-Heindl S, Cholet C, Scheidt HA, Beck-Sickinger AG, Meiler J, Huster D. Integrating solid state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin. PLoS One. 2015; 10:e0122444.

Schmidt P, Scheidt HA, Thomas L, Müller P, Huster D. The G protein-coupled neuropeptide Y receptor Type 2 is highly dynamic in lipid membranes. Chemistry. 2014; 20:4986-92.

Rose AS, Elgeti M, Zacchariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW. Position of transmembrane helix 6 determines receptor G-protein coupling specificity. J Am Chem Soc. 2014; 136:11244-7.

Scheerer P, Heck M, Goede A, Park JH, Choe HW, Ernst OP, Hofmann KP, Hildebrand PW. Structural and kinetic modeling of an activating helix switch in the rhodopsin-transducin interface. Proc Natl Acad Sci USA. 2009; 106:10660-5.