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
References
May 1, 1992·Immunology Today·L A Tartaglia, D V Goeddel
Mar 13, 1992·Science·B L KaganB J Wisnieski
Jul 9, 1991·International Journal of Cancer. Journal International Du Cancer·S NakamuraY Kohgo
Feb 1, 1990·The Journal of Experimental Medicine·T EspevikR Shalaby
Oct 25, 1991·Proceedings of the National Academy of Sciences of the United States of America·L A TartagliaD V Goeddel
Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·M BrockhausH Loetscher
May 25, 1990·Science·C A SmithR G Goodwin
Nov 1, 1990·The Journal of Experimental Medicine·M R ShalabyT Espevik
Aug 1, 1990·Protein Engineering·J YamagishiM Yamada
May 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·R G KilbournR F Lodato
Aug 1, 1990·Infection and Immunity·M P Chang, B J Wisnieski
May 1, 1989·Protein Engineering·R YamamotoL S Lin
Oct 1, 1989·Journal of Protein Chemistry·L O NarhiT Arakawa
Dec 19, 1985·Nature·B B AggarwalP E Hass
Apr 1, 1987·Journal of Biochemistry·M TsujimotoJ Vilcek
Jan 1, 1988·Annual Review of Biochemistry·B Beutler, A Cerami
Mar 24, 1988·Nature·L RiechmannG Winter
Dec 16, 1983·Journal of Immunological Methods·T Mosmann
Aug 25, 1980·Journal of Molecular Biology·M MarquartW Palm
Aug 1, 1995·European Journal of Immunology·M SchuchmannH Engelmann
Jan 1, 1994·Protein Engineering·X Van OstadeW Fiers
Mar 15, 1994·European Journal of Biochemistry·X Van OstadeW Fiers
Apr 1, 1994·The Journal of Experimental Medicine·K J Van ZeeD Stüber
Jan 21, 1993·Nature·X Van OstadeW Fiers
May 7, 1993·Cell·D W BannerW Lesslauer
Feb 6, 1996·Proceedings of the National Academy of Sciences of the United States of America·R L BaldwinB J Wisnieski
Apr 1, 1997·Proceedings of the National Academy of Sciences of the United States of America·M TaniyamaA Kaji
Jan 1, 1997·Anti-cancer Drugs·J SeongL Milas
Citations
Jul 13, 2000·Microscopy Research and Technique·H T Idriss, J H Naismith
Jun 22, 2000·Biotechnology and Bioengineering·D Y KimY H Park
Apr 26, 2006·Cancer Immunology, Immunotherapy : CII·Jeannette GerspachKlaus Pfizenmaier
Mar 10, 2011·Pharmaceutical Research·Michael James Wilson JohnstonMary Alice Hefford
Apr 28, 2000·Developmental and Comparative Immunology·G A Harrison, D N Wedlock
Mar 4, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Yohei MukaiYasuo Tsutsumi
Feb 5, 2011·Molekuliarnaia biologiia·T S NepomniashchikhS N Shchelkunov
Apr 4, 2002·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·E GarbuzenkoF Levi-Schaffer
Nov 28, 2015·Journal of Translational Medicine·Hemant Sarin
May 28, 2009·BMB Reports·Seung-Hwan JangHang-Cheol Shin
Dec 30, 2003·International Journal of Cancer. Journal International Du Cancer·Yuying LiuMichael G Rosenblum
Jan 12, 2019·Molecular Informatics·Urmi Roy
Jul 30, 2005·Cell Death and Differentiation·J GerspachK Pfizenmaier
Dec 8, 2015·Biochemistry and Molecular Biology Education : a Bimonthly Publication of the International Union of Biochemistry and Molecular Biology·Urmi Roy
Jul 27, 2017·The FEBS Journal·Vladimir N UverskyElrashdy M Redwan
Oct 10, 2014·PloS One·Grant E FrahmMichael J W Johnston
Mar 13, 2012·Journal of Molecular Recognition : JMR·Eric J BeilJennifer F Nemeth
Jun 30, 2016·Biotechnology and Applied Biochemistry·Urmi Roy
Feb 26, 1999·Analytical Biochemistry·Y J KimJ H Hahn
May 15, 2021·Developmental and Comparative Immunology·Yulu DuanChun Xia
Aug 23, 2006·Cytotherapy·Z YanY Zhang
Mar 20, 2012·The Journal of Physical Chemistry. B·Grant E FrahmMichael J W Johnston
Dec 2, 2017·Journal of the American Chemical Society·Daniela HofmannGerhard Wider
May 18, 2005·Biochemistry·Yeoun Jin KimJong Hoon Hahn