Structural, functional and evolutionary implications of the three-dimensional crystal structure of murine interferon-ß

Mitsui, Yukio; Senda, Toshiya; Shimazu, Tsuneo; Matsuda, Susumu; Utsumi, Jun

doi:10.1016/0163-7258(93)90068-o

Cited by 70 publications

(33 citation statements)

References 132 publications

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“…Glycosylation of huIFN-␤ is likely to play an important role in protein solubility and stability (31). It has been observed that nonglycosylated huIFN-␤ is much more susceptible to aggregation (17). Inspection of the crystal structure shows that there are a relatively high number of surface-exposed hydrophobic residues in the vicinity of the glycosylation site.…”

Section: Resultsmentioning

confidence: 99%

“…Although extensive structurefunction studies of ␣-IFNs employing mutagenesis and construction of hybrid molecules have been reported (reviewed in ref. 17), similar studies on IFN-␤ up to now have been limited to chemical mutagenesis (32) and alanine-scanning mutagenesis of loops AB (Arg-33 to Glu-41) and DE (Lys-134 to Ser-137) (unpublished data cited in ref. 5) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore it appears that the IFNreceptor complex may not be adequately described by a model similar to the HGH-receptor complex, a conclusion also reached in ref. 17 after examining mutagenesis data for HGH and granulocyte-macrophage colony-stimulating factor.…”

Section: Discussionmentioning

confidence: 99%

“…Comparing the three-dimensional structures and mutational analyses of the IFNs should yield insights into the molecular features determining their distinct biological activities. Despite extensive attempts, no crystals of human IFN-␤ had been previously obtained because of the tendency of protein produced in Escherichia coli to aggregate (17). Here, we report the crystallization and structure determination of glycosylated recombinant huIFN-␤, which was determined at 2.2-Å resolution by molecular replacement methods.…”

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confidence: 99%

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The crystal structure of human interferon β at 2.2-Å resolution

Karpusas

Nolte

Benton

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

196

130

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Type I interferons (IFNs) are helical cytokines that have diverse biological activities despite the fact that they appear to interact with the same receptor system. To achieve a better understanding of the structural basis for the different activities of ␣ and ␤ IFNs, we have determined the crystal structure of glycosylated human IFN-␤ at 2.2-Å resolution by molecular replacement. The molecule adopts a fold similar to that of the previously determined structures of murine IFN-␤ and human IFN-␣ 2b but displays several distinct structural features. Like human IFN-␣ 2b , human IFN-␤ contains a zinc-binding site at the interface of the two molecules in the asymmetric unit, raising the question of functional relevance for IFN-␤ dimers. However, unlike the human IFN-␣ 2b dimer, in which homologous surfaces form the interface, human IFN-␤ dimerizes with contact surfaces from opposite sides of the molecule. The relevance of the structure to the effects of point mutations in IFN-␤ at specific exposed residues is discussed. A potential role of ligand-ligand interactions in the conformational assembly of IFN receptor components is discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The crystal structure of human interferon β at 2.2-Å resolution

Karpusas

Nolte

Benton

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

196

130

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“…4 By induction of differentiation, S-phase accumulation, and apoptosis, 5 ± 7 IFN -can directly inhibit growth of tumor cells. 5,8 IFN -can also inhibit tumor growth and metastasis indirectly by activating the nitric oxide ( NO ) -dependent tumoricidal properties of macrophages, 9,10 by stimulating natural killer cells, 11,12 by suppressing angiogenic molecule expression, 13 ± 15 and by modulating T-cell ±mediated responses.…”

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confidence: 99%

Adenovirus-mediated interferon-β gene therapy suppresses growth and metastasis of human prostate cancer in nude mice

Cao

Wang

et al. 2001

Cancer Gene Ther

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The purpose of this study was to determine the effects of interferon -(IFN -) gene transfer on the growth of PC3MM2 human prostate cancer cells in nude mice. Intralesional delivery of an adenoviral vector encoding murine IFN -( AdIFN -) , but not a vector encoding bacterial -galactosidase ( AdLacZ ) , suppressed PC3MM2 tumors in a dose -dependent manner. At the highest dose ( 2Â10 9 plaque -forming units, PFU ) , a single injection of AdIFN -( but not AdLacZ ) suppressed orthotopic PC3MM2 tumors and development of metastasis by 80%, and eradicated the tumors in 20% of mice. Immunohistochemical staining showed that AdIFN -± treated tumors contained fewer microvessels, fewer proliferating cells, and more apoptotic cells than did the control tumors. Compared with controls, tumors injected with AdIFN -expressed higher levels of IFN -and inducible nitric oxide synthase ( iNOS ) and lower levels of basic fibroblast growth factor ( bFGF ) and transforming growth factor 1 ( TGF -1). In vitro analysis indicated that expression of bFGF and TGF -1 in PC3MM2 cells could be suppressed by the nitric oxide donor sodium nitroprusside. These data suggest that intratumoral delivery of the IFN -gene with adenoviral vectors could be an effective therapy for prostate cancer and that tumor suppression by AdIFN -correlated with up -regulation of iNOS and down -regulation of angiogenesis.

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The human interferon ? species and receptors

2000

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Interferon (IFN) was approved by the U.S. Food and Drug Administration on June 5, 1986. As the first biotherapeutic approved, IFN‐α paved the way for development of many other cytokines and growth factors. Nevertheless, we have just touched the surface of understanding the multitude of human IFNs. This paper reviews the history of the purification of human leukocyte IFN and key aspects of our current state of knowledge of human interferon α genes, proteins, and receptors. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 55: 254–287, 2000

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Structural, functional and evolutionary implications of the three-dimensional crystal structure of murine interferon-ß

Cited by 70 publications

References 132 publications

The crystal structure of human interferon β at 2.2-Å resolution

The crystal structure of human interferon β at 2.2-Å resolution

Adenovirus-mediated interferon-β gene therapy suppresses growth and metastasis of human prostate cancer in nude mice

The human interferon ? species and receptors

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