Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme
10.1073/pnas.95.7.3408
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

Tumor necrosis factor-α (TNFα) is a cytokine that induces protective inflammatory reactions and kills tumor cells but also causes severe damage when produced in excess, as in rheumatoid arthritis and septic shock. Soluble TNFα is released from its membrane-bound precursor by a membrane-anchored proteinase, recently identified as a multidomain metalloproteinase called TNFα-converting enzyme or TACE. We have cocrystallized the catalytic domain of TACE with a hydroxamic acid inhibitor and have solved its 2.0 Å crystal structure. This structure reveals a polypeptide fold and a catalytic zinc environment resembling that of the snake venom metalloproteinases, identifying TACE as a member of the adamalysin/ADAM family. However, a number of large insertion loops generate unique surface features. The pro-TNFα cleavage site fits to the active site of TACE but seems also to be determined by its position relative to the base of the compact trimeric TNFα cone. The active-site cleft of TACE shares properties with the matrix metalloproteinases but exhibits unique features such as a deep S3′ pocket merging with the S1′ specificity pocket below the surface. The structure thus opens a different approach toward the design of specific synthetic TACE inhibitors, which could act as effective therapeutic agents in vivo to modulate TNFα-induced pathophysiological effects, and might also help to control related shedding processes.

Bibliography

Maskos, K., Fernandez-Catalan, C., Huber, R., Bourenkov, G. P., Bartunik, H., Ellestad, G. A., Reddy, P., Wolfson, M. F., Rauch, C. T., Castner, B. J., Davis, R., Clarke, H. R. G., Petersen, M., Fitzner, J. N., Cerretti, D. P., March, C. J., Paxton, R. J., Black, R. A., & Bode, W. (1998). Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme. Proceedings of the National Academy of Sciences, 95(7), 3408–3412.

Authors 19
  1. Klaus Maskos (first)
  2. Carlos Fernandez-Catalan (additional)
  3. Robert Huber (additional)
  4. Gleb P. Bourenkov (additional)
  5. Hans Bartunik (additional)
  6. George A. Ellestad (additional)
  7. Pranitha Reddy (additional)
  8. Martin F. Wolfson (additional)
  9. Charles T. Rauch (additional)
  10. Beverly J. Castner (additional)
  11. Raymond Davis (additional)
  12. Howard R. G. Clarke (additional)
  13. Melissa Petersen (additional)
  14. Jeffrey N. Fitzner (additional)
  15. Douglas Pat Cerretti (additional)
  16. Carl J. March (additional)
  17. Raymond J. Paxton (additional)
  18. Roy A. Black (additional)
  19. Wolfram Bode (additional)
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Dates
Type When
Created 23 years, 1 month ago (July 26, 2002, 10:35 a.m.)
Deposited 3 years, 2 months ago (June 6, 2022, 10:56 p.m.)
Indexed 1 week, 1 day ago (Aug. 21, 2025, 2:17 p.m.)
Issued 27 years, 4 months ago (March 31, 1998)
Published 27 years, 4 months ago (March 31, 1998)
Published Online 27 years, 4 months ago (March 31, 1998)
Published Print 27 years, 4 months ago (March 31, 1998)
Funders 0

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@article{Maskos_1998, title={Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.7.3408}, DOI={10.1073/pnas.95.7.3408}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Maskos, Klaus and Fernandez-Catalan, Carlos and Huber, Robert and Bourenkov, Gleb P. and Bartunik, Hans and Ellestad, George A. and Reddy, Pranitha and Wolfson, Martin F. and Rauch, Charles T. and Castner, Beverly J. and Davis, Raymond and Clarke, Howard R. G. and Petersen, Melissa and Fitzner, Jeffrey N. and Cerretti, Douglas Pat and March, Carl J. and Paxton, Raymond J. and Black, Roy A. and Bode, Wolfram}, year={1998}, month=mar, pages={3408–3412} }