Description: Unravelling the Di- and Oligomerisation Interfaces of the G-Protein Coupled Bile Acid Receptor TGR5 via Integrative Modelling

This title appears in the Scientific Report : 2018

Unravelling the Di- and Oligomerisation Interfaces of the G-Protein Coupled Bile Acid Receptor TGR5 via Integrative Modelling

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 involve...

Personal Name(s):	Gertzen, C. G. W.
	Keitel, V. / Seidel, C. A. M. / Gohlke, H. (Corresponding author)
Contributing Institute:	Jülich Supercomputing Center; JSC Strukturbiochemie; ICS-6 John von Neumann - Institut für Computing; NIC
Imprint:	Jülich John von Neumann Institute for Computing 2018
Physical Description:	25 - 31
Conference:	NIC Symposium 2018, Jülich (Germany), 2018-02-22 - 2018-02-23
Document Type:	Contribution to a book Contribution to a conference proceedings
Research Program:	Energetics of the dimerization and G-protein coupling of the bile-acid sensing GPCR TGR5 Antagonists of the TGR5 G-protein complex formation Theory, modelling and simulation Physical Basis of Diseases Computational Science and Mathematical Methods
Series Title:	Publication Series of the John von Neumann Institute for Computing (NIC) NIC Series 49
Link:	OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://hdl.handle.net/2128/17547 in citations.

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.