Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom Resolution
10.1126/science.275.5307.1800
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

Protein farnesyltransferase (FTase) catalyzes the carboxyl-terminal lipidation of Ras and several other cellular signal transduction proteins. The essential nature of this modification for proper function of these proteins has led to the emergence of FTase as a target for the development of new anticancer therapy. Inhibition of this enzyme suppresses the transformed phenotype in cultured cells and causes tumor regression in animal models. The crystal structure of heterodimeric mammalian FTase was determined at 2.25 angstrom resolution. The structure shows a combination of two unusual domains: a crescent-shaped seven-helical hairpin domain and an α-α barrel domain. The active site is formed by two clefts that intersect at a bound zinc ion. One cleft contains a nine-residue peptide that may mimic the binding of the Ras substrate; the other cleft is lined with highly conserved aromatic residues appropriate for binding the farnesyl isoprenoid with required specificity.

Bibliography

Park, H.-W., Boduluri, S. R., Moomaw, J. F., Casey, P. J., & Beese, L. S. (1997). Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom Resolution. Science, 275(5307), 1800–1805.

Authors 5
  1. Hee-Won Park (first)
  2. Sobha R. Boduluri (additional)
  3. John F. Moomaw (additional)
  4. Patrick J. Casey (additional)
  5. Lorena S. Beese (additional)
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  59. Supported by NIH grant GM52382 Searle Scholar Foundation and Schering-Plough Research Institute to L.S.B. and by NIH grant GM46372 and Council for Tobacco Research grant 4064 to P.J.C. We thank G. Petsko for ethyl mercury phosphate A. Mondragon for advice on freezing FTase crystals J. Richardson for advice on structural homology and H. W. Hellinga for discussions and editorial assistance. We also thank the Keck Foundation for support of the Levine Science Research Center at Duke University. The coordinates have been deposited with the Brookhaven Protein Data Bank.
Dates
Type When
Created 23 years ago (July 27, 2002, 5:35 a.m.)
Deposited 1 year, 7 months ago (Jan. 12, 2024, 11 p.m.)
Indexed 2 weeks, 3 days ago (Aug. 5, 2025, 8:45 a.m.)
Issued 28 years, 5 months ago (March 21, 1997)
Published 28 years, 5 months ago (March 21, 1997)
Published Print 28 years, 5 months ago (March 21, 1997)
Funders 0

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@article{Park_1997, title={Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom Resolution}, volume={275}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.275.5307.1800}, DOI={10.1126/science.275.5307.1800}, number={5307}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Park, Hee-Won and Boduluri, Sobha R. and Moomaw, John F. and Casey, Patrick J. and Beese, Lorena S.}, year={1997}, month=mar, pages={1800–1805} }