Molecular dynamics analysis of farnesyltransferase: A closer look into the amino acid behavior

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Sergio F Sousa (Author) FCUP; Pedro A Fernandes (Author) FCUP; Maria Joao Ramos (Author) FCUP

Journal

Title: International Journal of Quantum Chemistry

Vol. 108

Pages: 1939-1950

ISSN: 0020-7608

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 9 Citations

Scopus - 11 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-003-WJ3

DOI: 10.1002/qua.21713

Abstract (EN): Farnesyltransferase (FTase) is a zinc enzyme that catalyzes the addition of a 15 carbons isoprenoid group from farnesyl diphosphate to protein substrates containing a typical -CAAX motif, where C is a cysteine residue. Among the possible CAAX substrates for FTase are a large number of biologically relevant proteins involved in cancer development, including the Ras family of proteins. FTase thus quickly became a very promising target for anticancer therapy, despite the fact that a number of questions regarding its catalytic activity have remained unexplained. This study describes the successful application of three sets of molecular dynamics parameters specifically designed to allow a reliable treatment of the zinc coordination sphere in the four key intermediate states formed during the catalytic cycle of this enzyme-FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-CAAX), and product complex-allowing a detailed analysis of the dynamic behavior of the several amino acid residues that constitute the enzyme, and complementing the more rigid time-averaged snapshot-view given by the available X-crystallographic structures with a more global structural vision that takes motion into account. (c) 2008 Wiley Periodicals, Inc.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12