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We have determined the structure of murine leukemia inhibitory factor (LIF) by X-ray crystallography at 2.0 A resolution. The current crystal structure comprises native LIF residues 9 to 180 with 40 ordered water molecules. For this model the R value (with a bulk solvent correction) is 18.6% on all data from 20.0 A to 2.0 A with stereochemistry typified by root mean square deviations from ideal bond lengths of 0.015 A. The mainchain fold conforms to the four alpha-helix bundle topology previously observed for several members of the hematopoietic cytokine family. Of these, LIF shows closest structural homology to granulocyte colony stimulating factor and growth hormone. Sequence alignments for the functionally related molecules oncostatin M and ciliary neurotrophic factor, when mapped to the LIF structure, indicate regions of conserved structural and surface character. Analysis of published mutagenesis data implicate two regions of receptor interaction which are located in the fourth helix and the preceding loop. A model for receptor binding based on the structure of the growth hormone ligand/receptor complex requires additional, novel features to account for these data.

Original publication

DOI

10.1111/j.1749-6632.1995.tb32325.x

Type

Journal article

Journal

Annals of the New York Academy of Sciences

Publication Date

07/1995

Volume

762

Pages

179 - 187

Addresses

Laboratory of Molecular Biophysics, University of Oxford, United Kingdom.

Keywords

Animals, Humans, Mice, Macromolecular Substances, Growth Inhibitors, Membrane Glycoproteins, Receptors, Cytokine, Recombinant Fusion Proteins, Antigens, CD, Interleukin-6, Lymphokines, Crystallography, X-Ray, Sequence Alignment, Amino Acid Sequence, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Structure-Activity Relationship, Molecular Sequence Data, Cytokine Receptor gp130, Leukemia Inhibitory Factor, Leukemia Inhibitory Factor Receptor alpha Subunit, Receptors, OSM-LIF