Crystal structure of the obese protein leptin-E100
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 ob...
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| Veröffentlicht in: | Nature (London) 1997-05, Vol.387 (6629), p.206-209 |
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| creator | ZHANG, F BASINSKI, M. B SCHONER, B. E SMITH, D. P ZHANG, X. Y WERY, J.-P SCHEVITZ, R. W BEALS, J. M BRIGGS, S. L CHURGAY, L. M CLAWSON, D. K DIMARCHI, R. D FURMAN, T. C HALE, J. E HSIUNG, H. M |
| description | 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. |
| doi_str_mv | 10.1038/387206a0 |
| format | Article |
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B ; SCHONER, B. E ; SMITH, D. P ; ZHANG, X. Y ; WERY, J.-P ; SCHEVITZ, R. W ; BEALS, J. M ; BRIGGS, S. L ; CHURGAY, L. M ; CLAWSON, D. K ; DIMARCHI, R. D ; FURMAN, T. C ; HALE, J. E ; HSIUNG, H. M</creator><creatorcontrib>ZHANG, F ; BASINSKI, M. B ; SCHONER, B. E ; SMITH, D. P ; ZHANG, X. Y ; WERY, J.-P ; SCHEVITZ, R. W ; BEALS, J. M ; BRIGGS, S. L ; CHURGAY, L. M ; CLAWSON, D. K ; DIMARCHI, R. D ; FURMAN, T. C ; HALE, J. E ; HSIUNG, H. M</creatorcontrib><description>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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/387206a0</identifier><identifier>PMID: 9144295</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing</publisher><subject>Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Animals ; Biological and medical sciences ; Body weight ; Central nervous system ; Conserved Sequence ; Crystalline structure ; Crystallization ; Crystallography, X-Ray ; Crystals ; Cytokines - chemistry ; Fundamental and applied biological sciences. Psychology ; Humans ; Infertility ; Leptin ; Miscellaneous ; Models, Molecular ; Molecular biophysics ; Molecular Sequence Data ; Mutation ; Obesity ; Protein Conformation ; Protein Structure, Secondary ; Proteins ; Proteins - chemistry ; Sequence Alignment ; Structure in molecular biology</subject><ispartof>Nature (London), 1997-05, Vol.387 (6629), p.206-209</ispartof><rights>1997 INIST-CNRS</rights><rights>Copyright Macmillan Journals Ltd. May 8, 1997</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2663985$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9144295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZHANG, F</creatorcontrib><creatorcontrib>BASINSKI, M. B</creatorcontrib><creatorcontrib>SCHONER, B. E</creatorcontrib><creatorcontrib>SMITH, D. P</creatorcontrib><creatorcontrib>ZHANG, X. Y</creatorcontrib><creatorcontrib>WERY, J.-P</creatorcontrib><creatorcontrib>SCHEVITZ, R. W</creatorcontrib><creatorcontrib>BEALS, J. M</creatorcontrib><creatorcontrib>BRIGGS, S. 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The structure reveals a four-helix bundle similar to that of the long-chain helical cytokine family.</description><subject>Amino Acid Sequence</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body weight</subject><subject>Central nervous system</subject><subject>Conserved Sequence</subject><subject>Crystalline structure</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray</subject><subject>Crystals</subject><subject>Cytokines - chemistry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Infertility</subject><subject>Leptin</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Molecular biophysics</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Obesity</subject><subject>Protein Conformation</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Proteins - chemistry</subject><subject>Sequence Alignment</subject><subject>Structure in molecular biology</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkEtLxDAUhYMo4zgK_gGhiOiqevNOllLGBwy40XVJ2wQ7dNqapIv590YsLlzo6izOx8e9B6FzDLcYqLqjShIQBg7QEjMpciaUPERLAKJyUFQco5MQtgDAsWQLtNCYMaL5EpHC70M0XRain-o4eZsNLovvKSobbDb6Idq2zzo7xrbP1xjgFB050wV7NucKvT2sX4unfPPy-Fzcb_KREh5zqZVTEurKKIytBCsawWnNG8MFYN1UEhpuLHOqBmm5E84pxpkwDidKG7pC19_edMPHZEMsd22obdeZ3g5TKKUGUAR4Am_-Bhnliksg_yoxT8NQ-aW8_AVuh8n36d2SAGNcEqITdDFDU7WzTTn6dmf8vpzHTf3V3JtQm85509dt-MGIEFQrTj8BxUuDtw</recordid><startdate>19970508</startdate><enddate>19970508</enddate><creator>ZHANG, F</creator><creator>BASINSKI, M. 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| ispartof | Nature (London), 1997-05, Vol.387 (6629), p.206-209 |
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| language | eng |
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| subjects | Amino Acid Sequence Analytical, structural and metabolic biochemistry Animals Biological and medical sciences Body weight Central nervous system Conserved Sequence Crystalline structure Crystallization Crystallography, X-Ray Crystals Cytokines - chemistry Fundamental and applied biological sciences. Psychology Humans Infertility Leptin Miscellaneous Models, Molecular Molecular biophysics Molecular Sequence Data Mutation Obesity Protein Conformation Protein Structure, Secondary Proteins Proteins - chemistry Sequence Alignment Structure in molecular biology |
| title | Crystal structure of the obese protein leptin-E100 |
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