Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: implications for cytokine receptor signaling

Protein Sci. 1997 May;6(5):999-1008. doi: 10.1002/pro.5560060505.


A conserved proline-rich motif (PRM) in the cytoplasmic domain of cytokine receptors has been suggested to be a signaling switch regulated by the action of the FK506 binding protein (FKBP) family of peptidylprolyl isomerases (O'Neal KD, Yu-Lee LY, Shearer WT, 1995, Ann NY Acad Sci 766:282-284). We have docked the prolactin receptor PRM (Ile1-Phe2-Pro3-Pro4-Val5-Pro6-Gly7-Pro8) to the ligand binding site of FKBP12. The procedure involved conformational search restricted by NMR restraints (O'Neal KD et al., 1996, Biochem J 315:833-844), energy minimization of the octapeptide conformers so obtained, template-based docking of a selected conformer to FKBP12, and energy refinement of the resulting complex. The template used was the crystal structure of a cyclic FK506-peptide hybrid bound to FKBP12. Val5-Pro6 of the PRM was taken to be the biologically relevant Xaa-Pro bond. The docked conformer is stabilized by two intramolecular hydrogen bonds, N7H7-->O4 and N2H2-->O8, and two intermolecular ones, Ile56; N-H-->O = C:Pro6 and Tyr82:O-H-->O = C:Gly7. This conformer features a Type I beta-turn and has extensive hydrophobic contacts with the FKBP12 binding surface. The observed interactions support the hypothesis that FKBP12 catalyzes cis-trans isomerization in the PRM when it is part of the longer cytoplasmic domain of a cytokine receptor, and suggest a significant role for the PRM in signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism*
  • Conserved Sequence
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Heat-Shock Proteins / chemistry*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Oligopeptides / chemistry*
  • Oligopeptides / metabolism
  • Proline*
  • Protein Conformation*
  • Protein Structure, Secondary
  • Receptors, Cytokine / chemistry*
  • Receptors, Cytokine / physiology*
  • Receptors, Prolactin / chemistry*
  • Receptors, Prolactin / metabolism*
  • Signal Transduction*
  • Tacrolimus / metabolism
  • Tacrolimus Binding Proteins
  • Templates, Genetic


  • Carrier Proteins
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Oligopeptides
  • Receptors, Cytokine
  • Receptors, Prolactin
  • Proline
  • Tacrolimus Binding Proteins
  • Tacrolimus