PDBsum entry 1ft4

Signaling protein

PDB id

1ft4

Contents

			Protein chain

					140 a.a. *

			Ligands

					703

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of tnf-Alpha.

Authors

P.H.Carter, P.A.Scherle, J.K.Muckelbauer, M.E.Voss, R.Q.Liu, L.A.Thompson, A.J.Tebben, K.A.Solomon, Y.C.Lo, Z.Li, P.Strzemienski, G.Yang, N.Falahatpisheh, M.Xu, Z.Wu, N.A.Farrow, K.Ramnarayan, J.Wang, D.Rideout, V.Yalamoori, P.Domaille, D.J.Underwood, J.M.Trzaskos, S.M.Friedman, R.C.Newton, C.P.Decicco, J.A.Muckelbauer.

Ref.

Proc Natl Acad Sci U S A, 2001, 98, 11879-11884. [DOI no: 10.1073/pnas.211178398]

PubMed id

11592999

Abstract

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.



	Figure 1. Fig. 1. Chemical structures of some optimized TNF- inhibitors.		Figure 6. Fig. 6. Superimposition of the crystal structures of IV703 bound to TNFRc1 (purple, this study) and that of TNF- bound to TNFRc1 (green; ref. 11). Note that Tyr-108 (TNF- ) normally interacts with Ala-62 (TNFRc1) (11); this receptor residue is bound to IV703 in our structure.