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Structures of Protein Farnesyltransferase

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Farnesyltransferase Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

High resolution three-dimensional crystal structures of protein farnesyltransferase (FTase) complexed with substrates and inhibitors provide a framework for understanding the molecular basis of substrate specificity and mechanism and may facilitate the development of improved chemotherapeutics. The 2.25Å resolution crystal structure of rat FTase provided the first structural information on any protein prenyltransferase enzyme (1). Rat FTase shares 93% sequence identity with the human enzyme and is predicted to be indistinguishable from human FTase in the active site region. Subsequently, a co-crystal structure of rat FTase with bound farnesyl diphosphate (FPP) revealed the location of the isoprenoid binding and gave insight into the molecular basis of isoprenoid substrate specificity (2). Recently, two co-crystal structures of rat FTase with a bound peptide substrate and a nonreactive isoprenoid diphosphate analog have identified the location of both the peptide and isoprenoid binding sites in a ternary enzyme complex (3,4). In this chapter we describe the recent crystal structures of rat FTase, and discuss their implications on understanding substrate specificity, mechanism, and inhibitor design.

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Authors
  1. Stephen B. Long PhD
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  2. Lorena S. Beese PhD
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Editor information

Editors and Affiliations

  1. H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

    Saïd M. Sebti PhD

  2. Department of Chemistry, Yale University, New Haven, CT, USA

    Andrew D. Hamilton PhD

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© 2001 Springer Science+Business Media New York

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Long, S.B., Beese, L.S. (2001). Structures of Protein Farnesyltransferase. In: Sebti, S.M., Hamilton, A.D. (eds) Farnesyltransferase Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-013-1_3

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  • DOI: https://doi.org/10.1007/978-1-59259-013-1_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9606-2

  • Online ISBN: 978-1-59259-013-1

  • eBook Packages: Springer Book Archive

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