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

K. V. Soman, B. A. Hanks, H. Tien, M. V. Chari, K. D. O'Neal, J. D. Morrisett

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4 Scopus citations

Abstract

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 → OC:Gly7. This conformer features a Type I β-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.

Original languageEnglish (US)
Pages (from-to)999-1008
Number of pages10
JournalProtein Science
Volume6
Issue number5
StatePublished - May 1997
Externally publishedYes

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Keywords

  • FK506
  • FK506 binding protein
  • immunosuppressant
  • molecular modeling
  • prolactin receptor
  • proline-rich motif
  • rapamycin
  • signaling

ASJC Scopus subject areas

  • Biochemistry

Cite this

Soman, K. V., Hanks, B. A., Tien, H., Chari, M. V., O'Neal, K. D., & Morrisett, J. D. (1997). Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: Implications for cytokine receptor signaling. Protein Science, 6(5), 999-1008.