Crystal structure of the obese protein Ieptin-E100

Faming Zhang, Margret B. Basinski, John M. Beals, Stephen L. Briggs, Lisa M. Churgay, David K. Clawson, Richard D. DiMarchi, Thomas C. Furman, John E. Hale, Hansen M. Hsiung, Brigitte E. Schoner, Dennis P. Smith, Xing Y. Zhang, Jean-Pierre Wery and Richard W. Schevitz
Additional contact information
Faming Zhang: Lilly Research Laboratories, Eli Lilly and Company
Margret B. Basinski: Lilly Research Laboratories, Eli Lilly and Company
John M. Beals: Lilly Research Laboratories, Eli Lilly and Company
Stephen L. Briggs: Lilly Research Laboratories, Eli Lilly and Company
Lisa M. Churgay: Lilly Research Laboratories, Eli Lilly and Company
David K. Clawson: Lilly Research Laboratories, Eli Lilly and Company
Richard D. DiMarchi: Lilly Research Laboratories, Eli Lilly and Company
Thomas C. Furman: Lilly Research Laboratories, Eli Lilly and Company
John E. Hale: Lilly Research Laboratories, Eli Lilly and Company
Hansen M. Hsiung: Lilly Research Laboratories, Eli Lilly and Company
Brigitte E. Schoner: Lilly Research Laboratories, Eli Lilly and Company
Dennis P. Smith: Lilly Research Laboratories, Eli Lilly and Company
Xing Y. Zhang: Lilly Research Laboratories, Eli Lilly and Company
Jean-Pierre Wery: Lilly Research Laboratories, Eli Lilly and Company
Richard W. Schevitz: Lilly Research Laboratories, Eli Lilly and Company

Nature, 1997, vol. 387, issue 6629, 206-209

Abstract: Abstract Mutations in the obese gene (OB) or in the gene encoding the OB receptor(OB-R) result in obesity, infertility and diabetes in a variety of mouse phenotypes1–7. The demonstration that OB protein (also known as leptin) can normalize body weight in ob/ob mice has generated enormous interest8–11. Most human obesity does not appear to result from a mutant form of leptin: rather, serum leptin concentrations are increased and there is an apparent inability to transport it to the central nervous system (CNS)12. Injection of leptin into the CNS of overfed rodents resistant to peripheral administration was found to induce biological activity13. Consequently, for the leptin to act as a weight-lowering hormone in human obesity, it appears that appropriate concentrations must be present in the CNS. This places a premium on understanding the structure of the hormone in order to design more potent and selective agonists. Here we report the crystal structure at 2.4 Å resolution of a human mutant OB protein (leptin-E100) that has comparable biological activity to wild type but which crystallizes more readily. The structure reveals a four-helix bundle similar to that of the long-chain helical cytokine family14.

Date: 1997
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DOI: 10.1038/387206a0

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