1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling.
Interleukin 6 (IL-6) has many biological activities in vivo, and deregulation has been implicated in many disease processes. IL-6, a 185 amino acid polypeptide was refolded, purified and crystallized. The crystals diffracted to beyond 1.9 A and the structure was solved using single isomorphous replacement. The X-ray structure of IL-6 is composed of a four helix bundle linked by loops and an additional mini-helix. 157 out of 185 residues are well defined in the final structure, with 18 N-terminal and 8 A-B loop amino acids displaying no interpretable electron density. The three-dimensional structure has been used to construct a model of IL-6 interacting with the IL-6 receptor (alpha-chain) and gp130 (beta-chain) that gives new insight into the process of molecular recognition and signaling. Based on this model, we predict a fourth binding site on IL-6, a low affinity IL-6-IL-6 interaction, which may be necessary for the sequential assembly of a functional hexameric IL-6 receptor complex.
Somers
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Small Molecule Drug Discovery, Genetics Institute, Inc., Cambridge, MA 02140, USA.
Stahl
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Seehra
J S
JS
D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry; D019382:Human Growth Hormone / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D014867:Water / Q000737:chemistry / Q000378:metabolism
D015703:Antigens, CD; D004220:Disulfides; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D014867:Water; D019382:Human Growth Hormone; D016179:Granulocyte Colony-Stimulating Factor