Project A02 – Investigation of the structure and dynamics of the ghrelin/GHS receptor complex
The peptide hormone ghrelin binds and activates the GHS receptor which is a key regulator of food uptake and body mass regulation. We study the conformational equilibria the GHS receptor undergoes during activation using experimental and computer simulation tools. We are particularly interested in a mechanistic understanding of the high basal activity of GHS receptor its downregulation holds pharmacological benefits. We will design peptidic ligands that may downregulate the basal activity of the receptor using modern computational tools and non-canonical amino acids.
Investigation of the structure and dynamics of the ghrelin/GHS receptor complex
Project Leader: Prof. Dr. Daniel Huster and Prof. Dr. Peter Hildebrand
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. Clara Tabea Schoeder (Project Leader)
Leipzig University, Faculty of Medicine
Institute for Drug Discovery
Liebigstrasse 19, 04103 Leipzig
Phone +49 341 97 25730
E-Mail
Web schoederlab.org/
Emelyn Pacull (PhD Student)
Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstrasse 16 – 18, 04107 Leipzig
Hannes Junker (PhD Student)
Leipzig University, Faculty of Medicine
Institute for Drug Discovery
Liebigstrasse 19, 04103 Leipzig
Resources
Structural dynamics of G-protein coupled receptors (GPCRs)
- Mechanism, specificity and dynamics of receptor-mediated signal transduction to G-proteins and arrestins using different molecular dynamics methods
- 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
Huster D, Maiti S, Herrmann A. Phospholipid Membranes as Chemically and Functionally Tunable Materials. Adv Mater. 2024 Mar 8:e2312898. doi: 10.1002/adma.202312898 
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Roy DS, Gozzi M, Engberg O, Adler J, Huster D, Maiti S. Membrane-Mediated Allosteric Action of Serotonin on a Noncognate G-Protein-Coupled Receptor. J Phys Chem Lett. 2024 Feb 15;15(6):1711-1718. doi: 10.1021/acs.jpclett.3c02340 .
Gupta A, Krupa P, Engberg O, Krupa M, Chaudhary A, Li MS, Huster D, Maiti S. Unusual Robustness of Neurotransmitter Vesicle Membranes against Sero-tonin-Induced Perturbations. J Phys Chem B. 2023; 127:1947-1955.
Papasergi-Scott MM, Pérez-Hernández G, Batebi H, Gao Y, Eskici G, Seven AB, Panova O, Hilger D, Casiraghi M, He F, Maul L, Gmeiner P, Kobilka BK, Hildebrand PW, Skiniotis G. Time-resolved cryo-EM of G protein activation by a GPCR. bioRxiv [Preprint]. 2023 Mar 21:2023.03.20.533387. doi: 10.1101/2023.03.20.533387. PMID: 36993214; PMCID: PMC10055275.
Schmidt P, Vogel A, Schwarze B, Seufert F, Licha K, Wycisk V, Kilian W, Hildebrand PW, Mitschang L. Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized 129Xe NMR. Molecules. 2023; 28(3):1424.
Smith AA, Pacull EM, Stecher S, Hildebrand PW, Vogel A, Huster D. Analysis of the Dynamics of the Human Growth Hormone Secretagogue Receptor Reveals Insights into the Energy Landscape of the Molecule. Angew Chem Int Ed Engl. 2023 May 19:e202302003. doi: 10.1002/anie.202302003. Epub ahead of print. PMID: 37205715.
Woods H, Schiano DL, Aguirre JI, Ledwitch KV, McDonald EF, Voehler M, Meiler J, Schoeder CT. Computational modeling and prediction of deletion mutants. Structure. 2023; S0969-2126(23)00128-4.
Kampfrath M, Staritzbichler R, Hernández GP, Rose AS, Tiemann JKS, Scheuermann G, Wiegreffe D, Hildebrand PW. MDsrv: visual sharing and analysis of molecular dynamics simulations. Nucleic Acids Res. 2022 May 26:gkac398. doi: 10.1093/nar/gkac398. Online ahead of print. PMID: 35639717.
Musabirova G, Engberg O, Gupta A, Roy DS, Maiti S, Huster D. Serotonergic drugs modulate the phase behavior of complex lipid bilayers. Biochimie. 2022 Apr 18:S0300-9084(22)00101-8. doi: 10.1016/j.biochi.2022.04.006. Online ahead of print. PMID: 35447219.
Smith AA, Vogel A, Engberg O, Hildebrand PW, Huster D. A method to construct the dynamic landscape of a bio-membrane with experiment and simulation. Nat Commun. 2022 Jan 10;13(1):108. doi: 10.1038/s41467-021-27417-y. PMID: 35013165; PMCID: PMC8748619.
Staritzbichler R, Yaklich E, Sarti E, Ristic N, Hildebrand PW, Forrest LR. AlignMe: an update of the web server for alignment of membrane protein sequences. Nucleic Acids Res. 2022 May 24:gkac391. doi: 10.1093/nar/gkac391. Online ahead of print. PMID: 35609986
Dey S, Surendran D, Engberg O, Gupta A, Fanibunda SE, Das A, Maity BK, Dey A, Visvakarma V, Kallianpur M, Scheidt HA, Walker G, Vaidya VA, Huster D, Maiti S. Altered Membrane Mechanics Provides a Receptor-Independent Pathway for Serotonin Action. Chemistry. 2021 May 12;27(27):7533-7541. doi: 10.1002/chem.202100328. Epub 2021 Mar 12. PMID: 33502812.
Bochicchio A, Brandner AF, Engberg O, Huster D, Böckmann RA. Spontaneous Membrane Nanodomain Formation in the Absence or Presence of the Neurotransmitter Serotonin. Front Cell Dev Biol. 2020 Nov 30;8:601145. doi: 10.3389/fcell.2020.601145. PMID: 33330494; PMCID: PMC7734319.
Engberg O, Bochicchio A, Brandner AF, Gupta A, Dey S, Böckmann RA, Maiti S, Huster D. Serotonin Alters the Phase Equilibrium of a Ternary Mixture of Phospholipids and Cholesterol. Front Physiol. 2020 Oct 23;11:578868. doi: 10.3389/fphys.2020.578868. PMID: 33192582; PMCID: PMC7645218.
Huster D. Structural dynamics of G protein-coupled receptors in lipid membranes investigated by solid-state NMR spectroscopy. in Solid-State NMR: Applications in Biomembrane Structure. Editors Frances Separovic and Marc-Antoine Sani IOP Publishing Ltd, 2020 (ISBN: 978-0-7503-2530-1), 11-1-11-27.
Krug U, Gloge A, Schmidt P, Becker-Baldus J, Bernhard F, Kaiser A, Montag C, Gauglitz M, Vishnivetskiy SA, Gurevich VV, Beck-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
Pacull EM, Sendker F, Bernhard F, Scheidt HA, Schmidt P, Huster D, Krug U. Integration of Cell-Free Expression and Solid-State NMR to Investigate the Dynamic Properties of Different Sites of the Growth Hormone Secretagogue Receptor. Front Pharmacol. 2020 Oct 29;11:562113. doi: 10.3389/fphar.2020.562113. PMID: 33324203; PMCID: PMC7723455.
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
Vogel A, Bosse M, Gauglitz M, Wistuba S, Schmidt P, Kaiser A, Gurevich VV, Beck-Sickinger AG, Hildebrand PW, Huster D. The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation. Molecules. 2020 Nov 24;25(23):5489. doi: 10.3390/molecules25235489. PMID: 33255213; PMCID: PMC7727705.
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 Y2. Angew 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.
