Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Applied Biosystems siRNA

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 21 March 1997:
Vol. 275. no. 5307, pp. 1800 - 1805
DOI: 10.1126/science.275.5307.1800
Prev | Table of Contents | Next

Reports

Crystal Structure of Protein Farnesyltransferase at 2.25 Angstrom Resolution

Hee-Won Park, Sobha R. Boduluri, John F. Moomaw, Patrick J. Casey, Lorena S. Beese *

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 alpha -alpha 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.

H.-W. Park, S. R. Boduluri, P. J. Casey, L. S. Beese, Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
J. F. Moomaw and P. J. Casey, Department of Molecular Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
*   To whom correspondence should be addressed.

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Novel Role for Protein Farnesylation in Plant Innate Immunity.
S. Goritschnig, T. Weihmann, Y. Zhang, P. Fobert, P. McCourt, and X. Li (2008)
Plant Physiology 148, 348-357
   Abstract »    Full Text »    PDF »
Metal active site elasticity linked to activation of homocysteine in methionine synthases.
M. Koutmos, R. Pejchal, T. M. Bomer, R. G. Matthews, J. L. Smith, and M. L. Ludwig (2008)
PNAS 105, 3286-3291
   Abstract »    Full Text »    PDF »
Farnesyl transferase inhibitor resistance probed by target mutagenesis.
T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley (2007)
Blood 110, 2102-2109
   Abstract »    Full Text »    PDF »
Identification of Essential Catalytic Residues of the Cyclase NisC Involved in the Biosynthesis of Nisin.
B. Li and W. A. van der Donk (2007)
J. Biol. Chem. 282, 21169-21175
   Abstract »    Full Text »    PDF »
A Defect in Protein Farnesylation Suppresses a Loss of Schizosaccharomyces pombe tsc2+, a Homolog of the Human Gene Predisposing to Tuberous Sclerosis Complex.
Y. Nakase, K. Fukuda, Y. Chikashige, C. Tsutsumi, D. Morita, S. Kawamoto, M. Ohnuki, Y. Hiraoka, and T. Matsumoto (2006)
Genetics 173, 569-578
   Abstract »    Full Text »    PDF »
Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I.
K. T. Lane and L. S. Beese (2006)
J. Lipid Res. 47, 681-699
   Abstract »    Full Text »    PDF »
Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis..
B. Li, J. P. J. Yu, J. S. Brunzelle, G. N. Moll, W. A. van der Donk, and S. K. Nair (2006)
Science 311, 1464-1467
   Abstract »    Full Text »    PDF »
SNOSID, a proteomic method for identification of cysteine S-nitrosylation sites in complex protein mixtures.
G. Hao, B. Derakhshan, L. Shi, F. Campagne, and S. S. Gross (2006)
PNAS 103, 1012-1017
   Abstract »    Full Text »    PDF »
Resistance to a Protein Farnesyltransferase Inhibitor in Plasmodium falciparum.
R. T. Eastman, J. White, O. Hucke, K. Bauer, K. Yokoyama, L. Nallan, D. Chakrabarti, C. L. M. J. Verlinde, M. H. Gelb, P. K. Rathod, et al. (2005)
J. Biol. Chem. 280, 13554-13559
   Abstract »    Full Text »    PDF »
Purification, Functional Reconstitution, and Characterization of the Saccharomyces cerevisiae Isoprenylcysteine Carboxylmethyltransferase Ste14p.
J. L. Anderson, H. Frase, S. Michaelis, and C. A. Hrycyna (2005)
J. Biol. Chem. 280, 7336-7345
   Abstract »    Full Text »    PDF »
Farnesyltransferase--New Insights into the Zinc-Coordination Sphere Paradigm: Evidence for a Carboxylate-Shift Mechanism.
S. F. Sousa, P. A. Fernandes, and M. J. Ramos (2005)
Biophys. J. 88, 483-494
   Abstract »    Full Text »    PDF »
Substrate binding mode and reaction mechanism of undecaprenyl pyrophosphate synthase deduced from crystallographic studies.
S.-Y. Chang, T.-P. Ko, A. P.-C. Chen, A. H.-J. Wang, and P.-H. Liang (2004)
Protein Sci. 13, 971-978
   Abstract »    Full Text »    PDF »
Mutagenesis Studies of Protein Farnesyltransferase Implicate Aspartate {beta}352 as a Magnesium Ligand.
J. S. Pickett, K. E. Bowers, and C. A. Fierke (2003)
J. Biol. Chem. 278, 51243-51250
   Abstract »    Full Text »    PDF »
Bornyl diphosphate synthase: Structure and strategy for carbocation manipulation by a terpenoid cyclase.
D. A. Whittington, M. L. Wise, M. Urbansky, R. M. Coates, R. B. Croteau, and D. W. Christianson (2002)
PNAS 99, 15375-15380
   Abstract »    Full Text »    PDF »
Role of the gamma Subunit Prenyl Moiety in G Protein beta gamma Complex Interaction with Phospholipase Cbeta.
V. C. Fogg, I. Azpiazu, M. E. Linder, A. Smrcka, S. Scarlata, and N. Gautam (2001)
J. Biol. Chem. 276, 41797-41802
   Abstract »    Full Text »    PDF »
The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.
S. B. Long, P. J. Hancock, A. M. Kral, H. W. Hellinga, and L. S. Beese (2001)
PNAS
   Abstract »    Full Text »    PDF »
Efficient Prenylation by a Plant Geranylgeranyltransferase-I Requires a Functional CaaL Box Motif and a Proximal Polybasic Domain.
D. Caldelari, H. Sternberg, M. Rodriguez-Concepcion, W. Gruissem, and S. Yalovsky (2001)
Plant Physiology 126, 1416-1429
   Abstract »    Full Text »    PDF »
Crystal structure of cis-prenyl chain elongating enzyme, undecaprenyl diphosphate synthase.
M. Fujihashi, Y.-W. Zhang, Y. Higuchi, X.-Y. Li, T. Koyama, and K. Miki (2001)
PNAS
   Abstract »    Full Text »
Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?.
C. W. M. Reuter, M. A. Morgan, and L. Bergmann (2000)
Blood 96, 1655-1669
   Abstract »    Full Text »    PDF »
Murine Guanylate-binding Protein: Incomplete Geranylgeranyl Isoprenoid Modification of an Interferon-gamma -inducible Guanosine Triphosphate-binding Protein.
J. T. Stickney and J. E. Buss (2000)
Mol. Biol. Cell 11, 2191-2200
   Abstract »    Full Text »
Cloning of the Arabidopsis WIGGUM gene identifies a role for farnesylation in meristem development.
E. C. Ziegelhoffer, L. J. Medrano, and E. M. Meyerowitz (2000)
PNAS
   Abstract »    Full Text »
Function and Mechanism of Zinc Metalloenzymes.
K. A. McCall, C.-c. Huang, and C. A. Fierke (2000)
J. Nutr. 130, 1437S-1446
   Abstract »    Full Text »
Protein Farnesylation Is Critical for Maintaining Normal Cell Morphology and Canavanine Resistance in Schizosaccharomyces pombe.
W. Yang, J. Urano, and F. Tamanoi (2000)
J. Biol. Chem. 275, 429-438
   Abstract »    Full Text »    PDF »
Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development.
E. K. Rowinsky, J. J. Windle, and D. D. Von Hoff (1999)
J. Clin. Oncol. 17, 3631-3652
   Abstract »    Full Text »    PDF »
A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors.
K. Del Villar, J. Urano, L. Guo, and F. Tamanoi (1999)
J. Biol. Chem. 274, 27010-27017
   Abstract »    Full Text »    PDF »
Role of Isoprenoid Lipids on the Heterotrimeric G Protein gamma  Subunit in Determining Effector Activation.
C.-S. Myung, H. Yasuda, W. W. Liu, T. K. Harden, and J. C. Garrison (1999)
J. Biol. Chem. 274, 16595-16603
   Abstract »    Full Text »    PDF »
High-level expression, purification, kinetic characterization and crystallization of protein farnesyltransferase ß-subunit C-terminal mutants.
Z. Wu, M. Demma, C. L. Strickland, R. Syto, H. V. Le, W. T. Windsor, and P. C. Weber (1999)
Protein Eng. Des. Sel. 12, 341-348
   Abstract »    Full Text »    PDF »
Single prenyl-binding site on protein prenyl transferases.
L. Desnoyers and M. C. Seabra (1998)
PNAS 95, 12266-12270
   Abstract »    Full Text »    PDF »
Protein Farnesyltransferase from Trypanosoma brucei. A HETERODIMER OF 61- AND 65-kDa SUBUNITS AS A NEW TARGET FOR ANTIPARASITE THERAPEUTICS.
K. Yokoyama, P. Trobridge, F. S. Buckner, W. C. Van Voorhis, K. D. Stuart, and M. H. Gelb (1998)
J. Biol. Chem. 273, 26497-26505
   Abstract »    Full Text »    PDF »
The LDL Receptor Clustering Motif Interacts with the Clathrin Terminal Domain in a Reverse Turn Conformation.
R. G. Kibbey, J. Rizo, L. M. Gierasch, and R. G.W. Anderson (1998)
J. Cell Biol. 142, 59-67
   Abstract »    Full Text »    PDF »
X-ray Crystal Structure of C3d: A C3 Fragment and Ligand for Complement Receptor 2 .
B. Nagar, R. G. Jones, R. J. Diefenbach, D. E. Isenman, and J. M. Rini (1998)
Science 280, 1277-1281
   Abstract »    Full Text »
Mutational Analysis of Conserved Residues of the beta -Subunit of Human Farnesyl:Protein Transferase.
A. M. Kral, R. E. Diehl, S. J. deSolms, T. M. Williams, N. E. Kohl, and C. A. Omer (1997)
J. Biol. Chem. 272, 27319-27323
   Abstract »    Full Text »    PDF »
Substrate specificity determinants in the farnesyltransferase beta -subunit.
C. E. Trueblood, V. L. Boyartchuk, and J. Rine (1997)
PNAS 94, 10774-10779
   Abstract »    Full Text »    PDF »
Structure and Function of a Squalene Cyclase.
K. U. Wendt, K. Poralla, and G. E. Schulz (1997)
Science 277, 1811-1815
   Abstract »    Full Text »
Cloning, Heterologous Expression, and Distinct Substrate Specificity of Protein Farnesyltransferase from Trypanosoma brucei.
F. S. Buckner, K. Yokoyama, L. Nguyen, A. Grewal, H. Erdjument-Bromage, P. Tempst, C. L. Strickland, L. Xiao, W. C. Van Voorhis, and M. H. Gelb (2000)
J. Biol. Chem. 275, 21870-21876
   Abstract »    Full Text »    PDF »
Overlapping Sites of Tetratricopeptide Repeat Protein Binding and Chaperone Activity in Heat Shock Protein 90.
A. J. Ramsey, L. C. Russell, S. R. Whitt, and M. Chinkers (2000)
J. Biol. Chem. 275, 17857-17862
   Abstract »    Full Text »    PDF »
Modification of Rab5 with a Photoactivatable Analog of Geranylgeranyl Diphosphate.
G. J. Quellhorst Jr., C. M. Allen, and M. Wessling-Resnick (2001)
J. Biol. Chem. 276, 40727-40733
   Abstract »    Full Text »    PDF »
Crystal structure of cis-prenyl chain elongating enzyme, undecaprenyl diphosphate synthase.
M. Fujihashi, Y.-W. Zhang, Y. Higuchi, X.-Y. Li, T. Koyama, and K. Miki (2001)
PNAS 98, 4337-4342
   Abstract »    Full Text »    PDF »
Cloning of the Arabidopsis WIGGUM gene identifies a role for farnesylation in meristem development.
E. C. Ziegelhoffer, L. J. Medrano, and E. M. Meyerowitz (2000)
PNAS 97, 7633-7638
   Abstract »    Full Text »    PDF »
The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.
S. B. Long, P. J. Hancock, A. M. Kral, H. W. Hellinga, and L. S. Beese (2001)
PNAS 98, 12948-12953
   Abstract »    Full Text »    PDF »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)