PDBsum entry 1ft4

Signaling protein

PDB id: 1ft4

Contents

Protein chain

140 a.a. *

Ligands

703

* Residue conservation analysis

PDB id:

1ft4

Name:

Signaling protein

Title:

Photochemically-enhanced binding of small molecules to the tumor necrosis factor receptor-1

Structure:

Soluble tumor necrosis factor receptor 1. Chain: a, b. Fragment: 55 kd extracellular domain (met plus residues 12-272). Synonym: tumor necrosis factor, binding protein 1, tbpi, p60, tnf-r1, tnf-ri, p55. Engineered: yes. Other_details: n of ala 62, chain a is bound to ligand 705

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.90Å R-factor: 0.274

Authors:

J.K.Muckelbauer,C.-H.Chang

Key ref:

P.H.Carter et al. (2001). Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha. Proc Natl Acad Sci U S A, 98, 11879-11884. PubMed id: 11592999 DOI: 10.1073/pnas.211178398

Date:

11-Sep-00 Release date: 12-Oct-01

Protein chains

P19438  (TNR1A_HUMAN) -  Tumor necrosis factor receptor superfamily member 1A from Homo sapiens

Seq: 455 a.a.

Struc: 140 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1073/pnas.211178398

Proc Natl Acad Sci U S A 98:11879-11884 (2001)

PubMed id: 11592999

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

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.

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.

Selected figure(s)

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.

Figures were selected by an automated process.