3l9j Citations

Selection of a novel and highly specific tumor necrosis factor alpha (TNFalpha) antagonist: insight from the crystal structure of the antagonist-TNFalpha complex.

J. Biol. Chem. 285 12096-100 (2010)
Cited: 7 times
EuropePMC logo PMID: 20179326


Inhibition of tumor necrosis factor alpha (TNFalpha) is a favorable way of treating several important diseases such as rheumatoid arthritis, Crohn disease, and psoriasis. Therefore, an extensive range of TNFalpha inhibitory proteins, most of them based upon an antibody scaffold, has been developed and used with variable success as therapeutics. We have developed a novel technology platform using C-type lectins as a vehicle for the creation of novel trimeric therapeutic proteins with increased avidity and unique properties as compared with current protein therapeutics. We chose human TNFalpha as a test target to validate this new technology because of the extensive experience available with protein-based TNFalpha antagonists. Here, we present a novel and highly specific TNFalpha antagonist developed using this technology. Furthermore, we have solved the three-dimensional structure of the antagonist-TNFalpha complex by x-ray crystallography, and this structure is presented here. The structure has given us a unique insight into how the selection procedure works at a molecular level. Surprisingly little change is observed in the C-type lectin-like domain structure outside of the randomized regions, whereas a substantial change is observed within the randomized loops. Thus, the overall integrity of the C-type lectin-like domain is maintained, whereas specificity and binding affinity are changed by the introduction of a number of specific contacts with TNFalpha.

Reviews citing this publication (3)

  1. Peptide aptamers: development and applications. Reverdatto S, Burz DS, Shekhtman A. Curr Top Med Chem 15 1082-1101 (2015)
  2. Non-immunoglobulin scaffolds: a focus on their targets. Škrlec K, Štrukelj B, Berlec A. Trends Biotechnol. 33 408-418 (2015)
  3. Challenges and opportunities for non-antibody scaffold drugs. Vazquez-Lombardi R, Phan TG, Zimmermann C, Lowe D, Jermutus L, Christ D. Drug Discov. Today 20 1271-1283 (2015)

Articles citing this publication (4)

  1. Structural basis for treating tumor necrosis factor α (TNFα)-associated diseases with the therapeutic antibody infliximab. Liang S, Dai J, Hou S, Su L, Zhang D, Guo H, Hu S, Wang H, Rao Z, Guo Y, Lou Z. J. Biol. Chem. 288 13799-13807 (2013)
  2. New binding mode to TNF-alpha revealed by ubiquitin-based artificial binding protein. Hoffmann A, Kovermann M, Lilie H, Fiedler M, Balbach J, Rudolph R, Pfeifer S. PLoS ONE 7 e31298 (2012)
  3. Structural pathways of cytokines may illuminate their roles in regulation of cancer development and immunotherapy. Guven-Maiorov E, Acuner-Ozbabacan SE, Keskin O, Gursoy A, Nussinov R. Cancers (Basel) 6 663-683 (2014)
  4. Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants. Willam A, Aufy M, Tzotzos S, Evanzin H, Chytracek S, Geppert S, Fischer B, Fischer H, Pietschmann H, Czikora I, Lucas R, Lemmens-Gruber R, Shabbir W. Front Pharmacol 8 85 (2017)