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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

Tacrolimus Binding Protein 1A
Prolactin Receptors
Cytokine Receptors
Proline
Tacrolimus Binding Proteins
Peptidylprolyl Isomerase
Cyclic Peptides
Signal transduction
Tacrolimus
Isomerization
Hydrogen
Signal Transduction
Hydrogen bonds
Crystal structure
Binding Sites
Switches
Nuclear magnetic resonance
Ligands

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.

Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12 : Implications for cytokine receptor signaling. / Soman, K. V.; Hanks, B. A.; Tien, H.; Chari, M. V.; O'Neal, K. D.; Morrisett, J. D.

In: Protein Science, Vol. 6, No. 5, 05.1997, p. 999-1008.

Research output: Contribution to journalArticle

Soman, KV, Hanks, BA, Tien, H, Chari, MV, O'Neal, KD & Morrisett, JD 1997, 'Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: Implications for cytokine receptor signaling', Protein Science, vol. 6, no. 5, pp. 999-1008.
Soman, K. V. ; Hanks, B. A. ; Tien, H. ; Chari, M. V. ; O'Neal, K. D. ; Morrisett, J. D. / Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12 : Implications for cytokine receptor signaling. In: Protein Science. 1997 ; Vol. 6, No. 5. pp. 999-1008.
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