Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists

Hudson, K R, Vernallis, Ann and Heath, J K (1996). Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists. Journal of Biological Chemistry, 271 (20), pp. 11971-8.

Abstract

Residues in human leukemia inhibitory factor (hLIF) crucial for binding to both the human LIF receptor (R) and gp130 were identified by analysis of alanine scanning mutants of hLIF in assays for both receptor binding and bioactivity. The region of hLIF most important for binding to the hLIF-R is composed of residues from the amino terminus of the D-helix, carboxyl terminus of the B-helix, and C-D loop. This site forms a distinct surface at the end of the four-helix bundle in the tertiary structure of the closely related murine LIF. The two residues of hLIF that contribute the majority of free energy for hLIF-R binding, Phe-156 and Lys-159 are surrounded by other residues which have only a moderate impact. This arrangement of a few key residues surrounded by less important ones is analogous to the functional binding epitope of human growth hormone for its receptor. A second region of hLIF that includes residues from the carboxyl terminus of the D-helix and A-B loop also had a weak influence on hLIF-R binding. Residues in hLIF from both the A- and C-helices are involved in binding the gp130 co-receptor. Abolition of the gp130 binding site in hLIF created antagonists of LIF action.

Publication DOI: https://doi.org/10.1074/jbc.271.20.11971
Divisions: Life & Health Sciences
Life & Health Sciences > Biosciences
Additional Information: © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Uncontrolled Keywords: Amino Acid Sequence,Base Sequence,Growth Inhibitors,Humans,Interleukin-6,Leukemia Inhibitory Factor,Leukemia Inhibitory Factor Receptor alpha Subunit,Lymphokines,Molecular Sequence Data,Mutagenesis,Receptors, Colony-Stimulating Factor,Receptors, Cytokine,Receptors, OSM-LIF,Structure-Activity Relationship
Full Text Link:
Related URLs: http://www.jbc. ... nt/271/20/11971 (Publisher URL)
Published Date: 1996-05-17
Authors: Hudson, K R
Vernallis, Ann
Heath, J K

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