Convergent Mechanisms for Recognition of Divergent Cytokines by the Shared Signaling Receptor gp130
Gp130 is a shared cell-surface signaling receptor for at least ten different hematopoietic cytokines, but the basis of its degenerate recognition properties is unknown. We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp...
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| Veröffentlicht in: | Molecular Cell 2003-09, Vol.12 (3), p.577-589 |
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| creator | Boulanger, Martin J Bankovich, Alexander J Kortemme, Tanja Baker, David Garcia, K.Christopher |
| description | Gp130 is a shared cell-surface signaling receptor for at least ten different hematopoietic cytokines, but the basis of its degenerate recognition properties is unknown. We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 Å resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a “thermodynamic plasticity” that is relatively insensitive to ligand structure, to enable crossreactivity. These observations reveal a novel and alternative mechanism for degenerate recognition from that of structural plasticity. |
| doi_str_mv | 10.1016/S1097-2765(03)00365-4 |
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We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 Å resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a “thermodynamic plasticity” that is relatively insensitive to ligand structure, to enable crossreactivity. 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We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 Å resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a “thermodynamic plasticity” that is relatively insensitive to ligand structure, to enable crossreactivity. These observations reveal a novel and alternative mechanism for degenerate recognition from that of structural plasticity.</description><subject>Animals</subject><subject>Antigens, CD - chemistry</subject><subject>Antigens, CD - immunology</subject><subject>Binding Sites - immunology</subject><subject>Cells, Cultured</subject><subject>Cross Reactions - immunology</subject><subject>Crystallography, X-Ray</subject><subject>Cytokine Receptor gp130</subject><subject>Cytokines - immunology</subject><subject>Eukaryotic Cells - immunology</subject><subject>Eukaryotic Cells - metabolism</subject><subject>Growth Inhibitors - chemistry</subject><subject>Growth Inhibitors - immunology</subject><subject>Immunity, Cellular - immunology</subject><subject>Insecta</subject><subject>Interleukin-6</subject><subject>Leukemia Inhibitory Factor</subject><subject>LYMPHOKINES</subject><subject>Lymphokines - chemistry</subject><subject>Lymphokines - immunology</subject><subject>Macromolecular Substances</subject><subject>Membrane Glycoproteins - chemistry</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>PARTICLE ACCELERATORS</subject><subject>Protein Binding - immunology</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Receptors, Cell Surface - chemistry</subject><subject>Receptors, Cell Surface - immunology</subject><subject>STANFORD LINEAR ACCELERATOR CENTER</subject><subject>STANFORD SYNCHROTRON RADIATION LABORATORY</subject><subject>SYNCHROTRON RADIATION</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtvGyEUhVHVqHn1J7SimyhZTALDwAyrqnKeUqJIcbJGDHNnTGuDAziS_30Y21GW3XAR-s49l3MR-kHJOSVUXEwpkXVR1oKfEnZGCBO8qL6gg81zRUX1dXcfkX10GONfQmjFG_kN7eda1hXhB8hMvHuDMIBL-AHMTDsbFxH3PuAnMH5wNlnvsO_xpf3gJuvk_1kHEbdrnGaApzMdoMNTOzg9t24YpbBMucewpIwco71ezyN839Uj9HJ99Ty5Le4fb-4mf-4Lw3mZipaUZVV3PYWaC655PhujS961uodeikbSlmtBoATGZVOJVjIjpGlLSnsmJTtCv7Z9fUxWRWNT_pDxzoFJqmE0u2TmZMssg39dQUxqYaOB-Vw78Kuo6mxLGzI241vQBB9jgF4tg13osFaUqHEDarMBNcarCFObDagq637uDFbtArpP1S7yDPzeApCjeLMQxknBGehsGAftvP2PxTsx7JUS</recordid><startdate>20030901</startdate><enddate>20030901</enddate><creator>Boulanger, Martin J</creator><creator>Bankovich, Alexander J</creator><creator>Kortemme, Tanja</creator><creator>Baker, David</creator><creator>Garcia, K.Christopher</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20030901</creationdate><title>Convergent Mechanisms for Recognition of Divergent Cytokines by the Shared Signaling Receptor gp130</title><author>Boulanger, Martin J ; 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We have determined the crystal structure of human leukemia inhibitory factor (LIF) bound to the cytokine binding region (CHR) of gp130 at 2.5 Å resolution. Strikingly, we find that the shared binding site on gp130 has an entirely rigid core, while the LIF binding interface diverges sharply in structure and chemistry from that of other gp130 ligands. Dissection of the LIF-gp130 interface, along with comparative studies of other gp130 cytokines, reveal that gp130 has evolved a “thermodynamic plasticity” that is relatively insensitive to ligand structure, to enable crossreactivity. These observations reveal a novel and alternative mechanism for degenerate recognition from that of structural plasticity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>14527405</pmid><doi>10.1016/S1097-2765(03)00365-4</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, CD - chemistry Antigens, CD - immunology Binding Sites - immunology Cells, Cultured Cross Reactions - immunology Crystallography, X-Ray Cytokine Receptor gp130 Cytokines - immunology Eukaryotic Cells - immunology Eukaryotic Cells - metabolism Growth Inhibitors - chemistry Growth Inhibitors - immunology Immunity, Cellular - immunology Insecta Interleukin-6 Leukemia Inhibitory Factor LYMPHOKINES Lymphokines - chemistry Lymphokines - immunology Macromolecular Substances Membrane Glycoproteins - chemistry Membrane Glycoproteins - immunology Models, Molecular Molecular Structure PARTICLE ACCELERATORS Protein Binding - immunology Protein Structure, Tertiary - physiology Receptors, Cell Surface - chemistry Receptors, Cell Surface - immunology STANFORD LINEAR ACCELERATOR CENTER STANFORD SYNCHROTRON RADIATION LABORATORY SYNCHROTRON RADIATION |
| title | Convergent Mechanisms for Recognition of Divergent Cytokines by the Shared Signaling Receptor gp130 |
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