High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity.

The Journal of Biological Chemistry
S S ChaB H Oh

Abstract

A human tumor necrosis factor-alpha (TNF-alpha) mutant (M3S) with low systemic toxicity in vivo was designed, and its structures in two different crystal packings were determined crystallographically at 1.8 and 2.15-A resolution, respectively, to explain altered biological activities of the mutant. M3S contains four changes: a hydrophilic substitution of L29S, two hydrophobic substitutions of S52I and Y56F, and a deletion of the N-terminal seven amino acids that is disordered in the structure of wild-type TNF-alpha. Compared with wild-type TNF-alpha, it exhibits 11- and 71-fold lower binding affinities for the human TNF-R55 and TNF-R75 receptors, respectively, and in vitro cytotoxic effect and in vivo systemic toxicity of M3S are 20 and 10 times lower, respectively. However, in a transplanted solid tumor mouse model, M3S suppresses tumor growth more efficiently than wild-type TNF-alpha. M3S is highly resistant to proteolysis by trypsin, and it exhibits increased thermal stability and a prolonged half-life in vivo. The L29S mutation causes substantial restructuring of the loop containing residues 29-36 into a rigid segment as a consequence of induced formation of intra- and intersubunit interactions, explaining the altered recep...Continue Reading

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Citations

Jul 13, 2000·Microscopy Research and Technique·H T Idriss, J H Naismith
Mar 10, 2011·Pharmaceutical Research·Michael James Wilson JohnstonMary Alice Hefford
Apr 28, 2000·Developmental and Comparative Immunology·G A Harrison, D N Wedlock
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May 15, 2021·Developmental and Comparative Immunology·Yulu DuanChun Xia
Dec 2, 2017·Journal of the American Chemical Society·Daniela HofmannGerhard Wider

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