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@INPROCEEDINGS{Gertzen:844071,
      author       = {Gertzen, C. G. W. and Keitel, V. and Seidel, C. A. M. and
                      Gohlke, H.},
      title        = {{U}nravelling the {D}i- and {O}ligomerisation {I}nterfaces
                      of the {G}-{P}rotein {C}oupled {B}ile {A}cid {R}eceptor
                      {TGR}5 via {I}ntegrative {M}odelling},
      volume       = {49},
      address      = {Jülich},
      publisher    = {John von Neumann Institute for Computing},
      reportid     = {FZJ-2018-01580},
      series       = {Publication Series of the John von Neumann Institute for
                      Computing (NIC) NIC Series},
      pages        = {25 - 31},
      year         = {2018},
      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.},
      month         = {Feb},
      date          = {2018-02-22},
      organization  = {NIC Symposium 2018, Jülich (Germany),
                       22 Feb 2018 - 23 Feb 2018},
      cin          = {JSC / NIC / ICS-6},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 553 - Physical Basis of Diseases (POF3-553) /
                      574 - Theory, modelling and simulation (POF3-574) /
                      Antagonists of the TGR5 G-protein complex formation
                      $(hdd15_20170501)$ / Energetics of the dimerization and
                      G-protein coupling of the bile-acid sensing GPCR TGR5
                      $(hdd15_20160501)$},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-553 /
                      G:(DE-HGF)POF3-574 / $G:(DE-Juel1)hdd15_20170501$ /
                      $G:(DE-Juel1)hdd15_20160501$},
      typ          = {PUB:(DE-HGF)8 / PUB:(DE-HGF)7},
      url          = {https://juser.fz-juelich.de/record/844071},
}