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 journalArticlepeer-review

    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
    DOIs
    StatePublished - May 1997

    Keywords

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

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology

    Fingerprint Dive into the research topics of 'Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: Implications for cytokine receptor signaling'. Together they form a unique fingerprint.

    Cite this