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@ARTICLE{Watkins:139938,
      author       = {Watkins, HA and Au, M and Bobby, R and Archbold, JK and
                      Abdul-Manan, N and Moore, JM and Middleditch, MJ and
                      Williams, GM and Brimble, MA and Dingley, Andrew and Hay,
                      DL},
      title        = {{I}dentification of key residues involved in adrenomedullin
                      binding to the {AM} 1 receptor},
      journal      = {British journal of pharmacology},
      volume       = {169},
      number       = {1},
      issn         = {0007-1188},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {FZJ-2013-05905},
      pages        = {143 - 155},
      year         = {2013},
      abstract     = {BACKGROUND AND PURPOSE:Adrenomedullin (AM) is a peptide
                      hormone whose receptors are members of the class B GPCR
                      family. They comprise a heteromer between the GPCR, the
                      calcitonin receptor-like receptor and one of the receptor
                      activity-modifying proteins 1-3. AM plays a significant role
                      in angiogenesis and its antagonist fragment AM22-52 can
                      inhibit blood vessel and tumour growth. The mechanism by
                      which AM interacts with its receptors is
                      unknown.EXPERIMENTAL APPROACH:We determined the AM22-52
                      binding epitope for the AM1 receptor extracellular domain
                      using biophysical techniques, heteronuclear magnetic
                      resonance spectroscopy and alanine scanning.KEY
                      RESULTS:Chemical shift perturbation experiments located the
                      main binding epitope for AM22-52 at the AM1 receptor to the
                      C-terminal 8 amino acids. Isothermal titration calorimetry
                      of AM22-52 alanine-substituted peptides indicated that Y52,
                      G51 and I47 are essential for AM1 receptor binding and that
                      K46 and P49 and R44 have a smaller role to play.
                      Characterization of these peptides at the full-length AM
                      receptors was assessed in Cos7 cells by cAMP assay. This
                      confirmed the essential role of Y52, G51 and I47 in binding
                      to the AM1 receptor, with their substitution resulting in
                      ≥100-fold reduction in antagonist potency compared with
                      AM22-52 . R44A, K46A, S48A and P49A AM22-52 decreased
                      antagonist potency by approximately 10-fold.CONCLUSIONS AND
                      IMPLICATIONS:This study localizes the main binding epitope
                      of AM22-52 to its C-terminal amino acids and distinguishes
                      essential residues involved in this binding. This will
                      inform the development of improved AM receptor antagonists.},
      cin          = {ICS-6},
      ddc          = {610},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {452 - Structural Biology (POF2-452)},
      pid          = {G:(DE-HGF)POF2-452},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000317679000011},
      doi          = {10.1111/bph.12118},
      url          = {https://juser.fz-juelich.de/record/139938},
}