1ft4: Difference between revisions

Revision as of 03:54, 1 July 2008

This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.

File:1ft4.png

Template:STRUCTURE 1ft4

PHOTOCHEMICALLY-ENHANCED BINDING OF SMALL MOLECULES TO THE TUMOR NECROSIS FACTOR RECEPTOR-1PHOTOCHEMICALLY-ENHANCED BINDING OF SMALL MOLECULES TO THE TUMOR NECROSIS FACTOR RECEPTOR-1

Template:ABSTRACT PUBMED 11592999

About this StructureAbout this Structure

1FT4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha., Carter PH, Scherle PA, Muckelbauer JK, Voss ME, Liu RQ, Thompson LA, Tebben AJ, Solomon KA, Lo YC, Li Z, Strzemienski P, Yang G, Falahatpisheh N, Xu M, Wu Z, Farrow NA, Ramnarayan K, Wang J, Rideout D, Yalamoori V, Domaille P, Underwood DJ, Trzaskos JM, Friedman SM, Newton RC, Decicco CP, Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):11879-84. PMID:11592999

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OCA

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-'''PHOTOCHEMICALLY-ENHANCED BINDING OF SMALL MOLECULES TO THE TUMOR NECROSIS FACTOR RECEPTOR-1'''
+===PHOTOCHEMICALLY-ENHANCED BINDING OF SMALL MOLECULES TO THE TUMOR NECROSIS FACTOR RECEPTOR-1===
-==Overview==
+<!--
-The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.
+The line below this paragraph, {{ABSTRACT_PUBMED_11592999}}, adds the Publication Abstract to the page
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 ==About this Structure==
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 [[Category: Binding protein]]
 [[Category: Cytokine]]
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