Protein Science, Vol 6, Issue 5 999-1008, Copyright © 1997 by Cold Spring Harbor Laboratory Press

ARTICLE

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 and J. D. MORRISETT
Departments of Medicine, Biochemistry, and Molecular Physiology/Biophysics, Baylor College of Medicine, Houston, Texas 77030

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 (Ile(1)-Phe(2)-Pro(3)-Pro(4)-Val(5)-Pro(6)-Gly(7)-Pro(8)) 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. Val(5)-Pro(6) of the PRM was taken to be the biologically relevant Xaa-Pro bond. The docked conformer is stabilized by two intramolecular hydrogen bonds, N(7)H(7) -> O(4) and N(2)H(2) -> O(8), and two intermolecular ones, Ile(56):N-H -> O=C:Pro(6) and Tyr(82):O-H -> O=C:Gly(7). 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.
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