2e7a
From Proteopedia
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'''TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity''' | '''TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity''' | ||
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[[Category: Tsutsumi, Y.]] | [[Category: Tsutsumi, Y.]] | ||
[[Category: Yamagata, Y.]] | [[Category: Yamagata, Y.]] | ||
| - | [[Category: | + | [[Category: Antagonistic activity]] |
| - | [[Category: | + | [[Category: Cytokine]] |
| - | [[Category: | + | [[Category: Phage display system]] |
| - | [[Category: | + | [[Category: Tnfr1 specific]] |
| - | [[Category: | + | [[Category: Trimer]] |
| - | [[Category: | + | [[Category: Tumor necrosis factor]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 02:03:47 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 23:03, 3 May 2008
TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity
Overview
Tumor necrosis factor-alpha (TNF) induces inflammatory response predominantly through the TNF receptor-1 (TNFR1). Thus, blocking the binding of TNF to TNFR1 is an important strategy for the treatment of many inflammatory diseases, such as hepatitis and rheumatoid arthritis. In this study, we identified a TNFR1-selective antagonistic mutant TNF from a phage library displaying structural human TNF variants in which each one of the six amino acid residues at the receptor-binding site (amino acids at positions 84-89) was replaced with other amino acids. Consequently, a TNFR1-selective antagonistic mutant TNF (R1antTNF), containing mutations A84S, V85T, S86T, Y87H, Q88N, and T89Q, was isolated from the library. The R1antTNF did not activate TNFR1-mediated responses, although its affinity for the TNFR1 was almost similar to that of the human wild-type TNF (wtTNF). Additionally, the R1antTNF neutralized the TNFR1-mediated bioactivity of wtTNF without influencing its TNFR2-mediated bioactivity and inhibited hepatic injury in an experimental hepatitis model. To understand the mechanism underlying the antagonistic activity of R1antTNF, we analyzed this mutant using the surface plasmon resonance spectroscopy and x-ray crystallography. Kinetic association/dissociation parameters of the R1antTNF were higher than those of the wtTNF, indicating very fast bond dissociation. Furthermore, x-ray crystallographic analysis of R1antTNF suggested that the mutation Y87H changed the binding mode from the hydrophobic to the electrostatic interaction, which may be one of the reasons why R1antTNF behaved as an antagonist. Our studies demonstrate the feasibility of generating TNF receptor subtype-specific antagonist by extensive substitution of amino acids of the wild-type ligand protein.
About this Structure
2E7A is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Creation and X-ray structure analysis of the tumor necrosis factor receptor-1-selective mutant of a tumor necrosis factor-alpha antagonist., Shibata H, Yoshioka Y, Ohkawa A, Minowa K, Mukai Y, Abe Y, Taniai M, Nomura T, Kayamuro H, Nabeshi H, Sugita T, Imai S, Nagano K, Yoshikawa T, Fujita T, Nakagawa S, Yamamoto A, Ohta T, Hayakawa T, Mayumi T, Vandenabeele P, Aggarwal BB, Nakamura T, Yamagata Y, Tsunoda S, Kamada H, Tsutsumi Y, J Biol Chem. 2008 Jan 11;283(2):998-1007. Epub 2007 Nov 14. PMID:18003610 Page seeded by OCA on Sun May 4 02:03:47 2008
