1a8m Citations

Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2.

Protein Eng. 10 1101-7 (1997)
Cited: 22 times
EuropePMC logo PMID: 9488135


Crystal structures have been determined of recombinant human tumor necrosis factor-alpha (TNF-alpha) and its R31D mutant that preferentially binds to TNF receptor R1 with more than seven times the relative affinity of binding to receptor R2. Crystals of the wild-type TNF were of space group P4(1)2(1)2 and had unit cell dimensions of a = b = 94.7 and c = 117.4 A. Refinement of the structure gave an R-factor of 22.3% at 2.5 A resolution. The crystals of TNF R31D mutant diffracted to 2.3 A resolution, and were of identical space group to the wild type with unit cell dimensions of a = b = 95.4 and c = 116.2 A, and the structure was refined to an R-factor of 21.8%. The trimer structures of the wild-type and mutant TNF were similar with a root mean square (r.m.s.) deviation of 0.56 A for Calpha atoms; however, the subunits within each trimer were more variable with an average r.m.s. deviation of 1.00 A on Calpha atoms for pairwise comparison of subunits. Model complexes of TNF with receptors R1 and R2 have been used to predict TNF-receptor interactions. Arg31 in all three subunits of wild-type TNF is predicted to form an ionic interaction with the equivalent glutamic acid in both receptors R1 and R2. Asp31 of the TNF R31D mutant is predicted to interact differently with the two receptors. The side chain of Asp31 in two subunits of the TNF mutant is predicted to form hydrogen bond interactions with Ser59 or Cys70 of R1, while it has no predicted interactions with R2. The loss of three strong ionic interactions of Arg31 and the electrostatic repulsion of Asp31 with Glu in the receptors is consistent with the reduced binding of the R31D mutant to both receptors relative to wild-type TNF. The replacement of these ionic interactions by two weaker hydrogen bond interactions between Asp31 of the R31D mutant and R1, compared with no interactions with R2, is in agreement with the observed preferential binding of the R31D mutant to R1 over R2. Analysis of the structure and function of receptor-discriminating mutants of TNF will help understand the biological role of TNF and facilitate its use as an antitumor agent.

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  2. Highly precise protein-protein interaction prediction based on consensus between template-based and de novo docking methods. Ohue M, Matsuzaki Y, Shimoda T, Ishida T, Akiyama Y. BMC Proc 7 S6 (2013)

Reviews citing this publication (1)

  1. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Idriss HT, Naismith JH. Microsc. Res. Tech. 50 184-195 (2000)

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  13. The protective antibodies induced by a novel epitope of human TNF-alpha could suppress the development of collagen-induced arthritis. Dong J, Gao Y, Liu Y, Shi J, Feng J, Li Z, Pan H, Xue Y, Liu C, Shen B, Shao N, Yang G. PLoS ONE 5 e8920 (2010)
  14. Hydrophobic cavity in C-terminus is essential for hTNF-α trimer conformation. Liu H, Dai L, Hao Z, Huang W, Yang Q. Biochimie 94 1001-1008 (2012)
  15. Fullerenes and their derivatives as inhibitors of tumor necrosis factor-α with highly promoted affinities. Wu G, Gao XJ, Jang J, Gao X. J Mol Model 22 161 (2016)
  16. Pharmacological basis of the use of the root bark of Zizyphus nummularia Aubrev. (Rhamnaceae) as anti-inflammatory agent. Ray SD, Ray S, Zia-Ul-Haq M, De Feo V, Dewanjee S. BMC Complement Altern Med 15 416 (2015)
  17. Identification of the RNA chaperone activity of recombinant human tumor necrosis factor alpha in vitro. Cao G, Yang G, Liu Z, Liu X, Zhang J, Zhang D, Liu N, Ding H, Fan M, Shen B, Shao N. Biochem. Biophys. Res. Commun. 328 573-579 (2005)
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  1. Model Complexes of Tumor Necrosis Factor-Alpha with Receptors R1 and R2. Fu ZQ, Harrison RW, Reed C, Wu J, Xue YN, Chen MJ, Weber IT Protein Eng. 8 1233- (1995)