Interleukin structure

Figure 9 Relative accuracy of comparative models. Upper left panel, comparison of homologous structures that share 40% sequence identity. Upper right panel, conformations of ileal lipid-binding protein that satisfy the NMR restraints set equally well. Lower left panel, comparison of two independently determined X-ray structures of interleukin 1(3. Lower right panel, comparison of the X-ray and NMR structures of erabutoxin. The figure was prepared using the program MOLSCRIPT [236].

DPI Ohlendorf. Accuracy of refined protein structures. II. Comparison of four independently refined models of human interleukin 1(1. Acta Cryst 050 808-812, 1994. 

Vigers, G.P.A., et al. Crystal structure of the type-1 interleukin-1 receptor complexed with interleukin-ip. Nature 386 190-194, 1997. 

Cytokine receptors are a group of structurally related receptors, which couple to the JAK-STAT pathway. Cytokine receptors function as homodimers or heterooligomers. They are divided into two main subclasses, class I, which contains receptors for a variety of hematopoietic growth factors and interleukins and class II, which contains receptors for interferons and interleukins 10, 20/24 and 22. 

Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-a (TNF-a). Various proteinases, such as elastase, cathepsin G, and proteinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures. 

Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI. Structure and functional expression of a human interleukin-8 receptor. Science 1991 253 1278-1280. 

Clore GM, Appella E, Yamada M, Matsushima K, Gronenbom AM. Three-dimensional structure of interleukin 8 in solution. Biochemistry 1990 29 1689-96. 

Skelton NJ, Quan C, Reilly D, Lowman H. Structure of a CXC chemokine-receptor fragment in complex with interleukin-8. Structure 1999 7 157-68. 

Clark-Lewis I, Schumacher C, Baggiofini M, Moser B. Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemo-taxis, exocytosis, and receptor binding activities. J Biol Chem 1991 266 23128-34. 

Figure 2.8 Three-dimensional structure of (a) human interleukin-4, as determined by NMR, and (b) human follicle-stimulating hormone, as determined by X-ray diffraction. Reproduced from protein data bank (www. rcsb.org/pdb, molecule ID numbers 1ITM and 1 FL7 respectively)...

FIGURE 27-3 Neurotrophic cytokines and their receptors. Neurotrophic cytokines are related to IL6 and bind to cell surface receptor complexes that share a common structural organization. The four ligands interchangeably employ two distinct receptor subunits, leukemia inhibitory factor receptor 3 (LIF-Rpt) andgpl30, and some employ a ligand-specific a subunit. CNTF-R, ciliary neurotrophic factor CT-fR.cardiotrophin 1 receptor IL6-R, interleukin-6 receptor. 

Pietzko, D. et al., The hepatic interleukin-6 receptor. Studies on its structure and regulation by phorbol 12-myristate 13-acetate-dexamethasone, J. Biol. Chem., 268, 4250, 1993. 

Feng Y., Klein B.K., and McWherter C.A. (1996), Three-dimensional solution structure and backbone dynamics of a variant of human interleukin-3,./. Mol. Biol. 259, 524-541. 

Van den Berg A, Ruiper M, Snoek M, Timens W, Postma DS, Jansen HM, Lutter R Interleukin-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells. Am J Respir Cell Mol Biol 2005 33 97-104. 

The biological activities of several other interleukins also render them likely candidates for therapeutic application. IL-5 represents one such candidate. IL-5 is a 115 amino acid glycoprotein produced mainly by activated T lymphocytes and also by mast cells. It functions as a homodimer, exhibiting a molecular mass of 45 kDa. The individual polypeptide chains interact non-covalently and the overall dimeric structure is stabilized by two interchain disulphide linkages between cysteines 42 and 84 of each chain. Removal or alterations of the cytokine s carbohydrate side-chain does not appear to affect its biological activity. 

Powers, R., Garrett, D.S., March, C.l. et al. (1992). Three-dimensional solution structure of human interleukin-4 by multidimensional heteronuclear magnetic resonance spectroscopy. Science 256, 1673. 

Remarkably, incorporation of fluorinated amino acids into proteins can also be accomplished in vivo. This supposes that the fluorinated amino acid analogs are recognized by the appropriate amino acyl-tRNA synthetase enzyme with efficiency similar to that of the natural amino acid. The proliferase response elicited by a fluorinated analog (a trifluoroisoleucine derivative) of murine interleukin-2 produced in an appropriate Escherichia coli strain was nearly as high as that of the authentic cytokine, indicating folding into an authentic, native structure [84],... 

Fig. 11.2. Domain structure of cytokine receptors. Schematic representation of the domain structure of selected cytokine receptors. WS motif conserved WSXWS sequence (W tryptophan S serine X non-conserved amino add) IL interleukin EpoR receptor for erythropoietin GHR growth hormone receptor LIF-R leukemia inhibitory factor receptor G-CSFR granulocyte colony stimulating factor receptor IFNR interferon receptor TNFR tumor necrosis factor receptor NGFR nerve growth factor receptor Fas, CD40 transmembrane receptors of lymphocytes.

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