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|1ax8, resolution 2.40Å ()|
|Gene:||OBESE GENE (Homo sapiens)|
Human obesity protein, leptin
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 phenotypes. The demonstration that OB protein (also known as leptin) can normalize body weight in ob/ob mice has generated enormous interest. 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). Injection of leptin into the CNS of overfed rodents resistant to peripheral administration was found to induce biological activity. 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 2.4A 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 family.
Crystal structure of the obese protein leptin-E100., Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW, Nature. 1997 May 8;387(6629):206-9. PMID:9144295
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[LEP_HUMAN] Defects in LEP may be a cause of obesity (OBESITY) [MIM:601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.
[LEP_HUMAN] May function as part of a signaling pathway that acts to regulate the size of the body fat depot. An increase in the level of LEP may act directly or indirectly on the CNS to inhibit food intake and/or regulate energy expenditure as part of a homeostatic mechanism to maintain constancy of the adipose mass.
About this Structure
1ax8 is a 1 chain structure with sequence from Homo sapiens. The May 2012 RCSB PDB Molecule of the Month feature on Leptin by David Goodsell is 10.2210/rcsb_pdb/mom_2012_5. Full crystallographic information is available from OCA.
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- Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW. Crystal structure of the obese protein leptin-E100. Nature. 1997 May 8;387(6629):206-9. PMID:9144295 doi:10.1038/387206a0
- Shortle D. Composites of local structure propensities: evidence for local encoding of long-range structure. Protein Sci. 2002 Jan;11(1):18-26. PMID:11742118