1ft4

From Proteopedia

---

Revision as of 14:50, 12 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 1ft4, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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.

Disease

Known diseases associated with this structure: Periodic fever, familial OMIM:[191190]

About this Structure

1FT4 is a Single protein structure of sequence from Homo sapiens with 703 as ligand. Full crystallographic information is available from OCA.

Reference

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

Page seeded by OCA on Mon Nov 12 16:57:13 2007