Contribution to a conference proceedings/Contribution to a book

FZJ-2018-01580

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Unravelling the Di- and Oligomerisation Interfaces of the G-Protein Coupled Bile Acid Receptor TGR5 via Integrative Modelling

Gertzen, C. G. W. ; Keitel, V. ; Seidel, C. A. M. ; Gohlke, H. (Corresponding author)FZJ*

2018
John von Neumann Institute for Computing Jülich

Please use a persistent id in citations: http://hdl.handle.net/2128/17547

Abstract: TGR5 is a bile acid- and neurosteroid-sensing G-protein coupled receptor (GPCR), which isalmost ubiquitously expressed throughout the human body. Its physiological functions comprisethe regulation of blood glucose homeostasis, metabolism, and inflammation. Additionally,recent studies show an involvement of TGR5 in the formation of gastric, esophageal, andcholangiocyte cancers as well as in bile acid-induced itch. Hence, TGR5 has been identified asan important drug target. To reduce side effects of drugs targeting GPCRs, the development ofbivalent ligands specifically targeting dimers was shown to be promising. To do so, the knowledgeof the dimerisation interfaces of these GPCRs is paramount. However, the dimerisationinterfaces of TGR5 are not known. Here, we present the identification of the primary dimerisationinterface of TGR5 and possible oligomerisation interfaces. We used Multiparameter ImageFluorescence Spectroscopy (MFIS) Förster Resonance Energy Transfer (FRET) measurementsof fluorescently labelled TGR5 in live cells to measure apparent distances between two TGR5protomers and compared them to distances computed for putative TGR5 dimer models. Asthe linker between TGR5 and the fluorophores contained more than 30 residues, we used all-atommolecular dynamics (MD) simulations to sample the conformational space of the linkerand fluorophore in relation to TGR5. The sampled configurations were reweighted by free energycalculations using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)method to account for the presence of solvent and a membrane, and a random energy model toestimate the configurational entropy. This allowed us to identify the 1-8 interface of TGR5 asthe primary dimerisation interface, with the 4-5 and 5-6 interfaces as possible oligomerisationsites. This information might be used to develop novel TGR5 ligands with a reduced side-effectprofile.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (ICS-6)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. 553 - Physical Basis of Diseases (POF3-553) (POF3-553)
3. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
4. Antagonists of the TGR5 G-protein complex formation (hdd15_20170501) (hdd15_20170501)
5. Energetics of the dimerization and G-protein coupling of the bile-acid sensing GPCR TGR5 (hdd15_20160501) (hdd15_20160501)

Appears in the scientific report 2018

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Database coverage:

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Book/Proceedings Binder, K. (Editor) ; Müller, M. (Editor) ; Trautmann, A. (Editor)FZJ*
NIC Symposium 2018
2018NIC Symposium, JülichJülich, Germany, 22 Feb 2018 - 23 Feb 20182018-02-222018-02-23 Jülich : Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag, NIC Series 49, VI, 448 S. (2018)2018   Files  Fulltext by OpenAccess repository BibTeX | EndNote: XML, Text | RIS

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