Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: Implications for TNF receptor activation

Banner, David W.; D’Arcy, Allan; Janes, Wolfgang; Gentz, Reiner; Schoenfeld, Hans-Joachim; Broger, Clemens; Loetscher, Hansruedi; Lesslauer, Werner

doi:10.1016/0092-8674(93)90132-a

Cited by 1,055 publications

(840 citation statements)

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“…Based on x-ray crystallographic information about the TNF␤-TNFRI complex (11) and about TNF␣ itself (12), the critical binding site on TNFRI was clarified. The aromatically modified exocyclic analog type of TNF inhibitor was then designed to mimic the 3-dimensional structure of the critical region, interfering with TNF␣-TNFR interactions (10).…”

mentioning

confidence: 99%

A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis

Saito

Kojima

Takahashi

et al. 2007

Arthritis & Rheumatism

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Objective. The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor ␣ (TNF␣) recognition loop on TNF receptor I, and it prevents interactions of TNF␣ with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen-induced arthritis (CIA) in mice with those of anti-TNF␣ monoclonal antibody.Methods. CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti-TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed.Results. WP9QY treatment inhibited CIAinduced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti-TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA-induced bone destruction at the knee joints to the same extent as did anti-TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA-induced systemic bone loss by WP9QY was more apparent than that by anti-TNF antibody.Conclusion. The TNF␣ antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.

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confidence: 99%

A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis

Saito

Kojima

Takahashi

et al. 2007

Arthritis & Rheumatism

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“…These proteins share little primary sequence similarity in their extracellular domains, apart from the cysteine pattern. The X-ray structure of the TNFR was first determined as part of a complex with TNF-,B (Banner et al, 1993), and subsequently in the unliganded state at pH 7.5 (Naismith et al, 1995). The extracellular region of TNFR is composed of four domains of 44 amino acids.…”

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confidence: 99%

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

et al. 1998

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CD40 Ligand (CD40L) is transiently expressed on the surface of T-cells and binds to CD40, which is expressed on the surface of B-cells. This binding event leads to the differentiation, proliferation, and isotype switching of the B-cells. The physiological importance of CD40L has been demonstrated by the fact that expression of defective CD40L protein causes an immunodeficiency state characterized by high IgM and low IgG serum levels, indicating faulty T-cell dependent B-cell activation. To understand the structural basis for CD40L/CD40 association, we have used a combination of molecular modeling, mutagenesis, and X-ray crystallography. The structure of the extracellular region of CD4OL was determined by protein crystallography, while the CD40 receptor was built using homology modeling based upon a novel alignment of the TNF receptor superfamily, and using the X-ray structure of the TNF receptor as a template. The model shows that the interface of the complex is composed of charged residues, with CD4OL presenting basic side chains (K143, R203, R207), and CD40 presenting acidic side chains (D84, El 14, E l 17). These residues were studied experimentally through site-directed mutagenesis, and also theoretically using electrostatic calculations with the program Delphi. The mutagenesis data explored the role of the charged residues in both CD40L and CD40 by switching to Ala (K143A, R203A, R207A of CD40L, and E74A, D84A, El14A, E l 17A of CD40), charge reversal (K143E, R203E, R207E of CD40L, and D84R, E l 14R, El 17R of CD40), mutation to a polar residue (K143N, R207N, R207Q of C340L, and D84N, E l 17N of CD40), and for the basic side chains in CD40L, isosteric substitution to a hydrophobic side chain (R203M, R207M). All the charge-reversal mutants and the majority of the Met and Ala substitutions led to loss of binding, suggesting that charged interactions stabilize the complex. This was supported by the Delphi calculations which confirmed that the CD40/CD40L residue pairs E74-R203, D84-R207, and El 17-R207 had a net stabilizing effect on the complex. However, the substitution of hydrophilic side chains at several of the positions was tolerated, which suggests that although charged interactions stabilize the complex, charge per se is not crucial at all positions. Finally, we compared the electrostatic surface of TNFjTNFR with CD40L/CD40 and have identified a set of polar interactions surrounded by a wall of hydrophobic residues that appear to be similar but inverted between the two complexes.

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“…Under similar conditions, receptor aggregation was observed in crystals of receptor-ligand complexes of the human growth hormone receptor [18] and the tumor necrosis factor receptor [19]. If the IL-lra molecule would cause aggregation of IL-1 receptor molecules, we would expect to see this aggregation in the crystals.…”

Section: Discussionmentioning

confidence: 79%

Crystals of soluble interleukin‐1 receptor complexed with its natural antagonist reveal a 1:1 receptor‐ligand complex

Schreuder¹,

Tardif²,

Soffientini³

et al. 1995

FEBS Letters

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Interleukin-1 is a cytokine involved in the acute phase response against infection and injury. We obtained crystals of a complex of soluble, recombinant human interleukin-1 receptor and recombinant human interleukin-1 receptor antagonist, a naturally occurring antagonist. ° The crystals are suitable for X-ray analysis and diffract to 2.7 A resolution. Solvent content calculations indicate that the crystals contain one receptor and one antagonist molecule per asymmetric unit. Other receptor to antagonist ratios are highly unlikely. These results suggest that the interleukin-1 antagonist binds a single receptor molecule and does not cause receptor aggregation.

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Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: Implications for TNF receptor activation

Cited by 1,055 publications

References 50 publications

A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis

A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

Crystals of soluble interleukin‐1 receptor complexed with its natural antagonist reveal a 1:1 receptor‐ligand complex

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