Theoretical studies on farnesyltransferase: The distances paradox explained

• Type: Another Publication in an International Scientific Journal
• Date: 2007

Authors

Sergio Filipe Sousa (Author) Other; Pedro Alexandrino Fernandes (Author) FCUP; Maria Joao Ramos (Author) FCUP

Journal

Title: Proteins: Structure, Function and Genetics

Vol. 66

Pages: 205-218

ISSN: 0887-3585

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 37 Citations

Scopus - 41 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-004-EGB

DOI: 10.1002/prot.21219

Abstract (EN): In spite of the enormous interest that has been devoted to its study, the mechanism of the enzyme farnesyltransferase (FTase) remains the subject of several crucial doubts. In this article, we shed a new light in one of the most fundamental dilemmas that characterize the mechanism of this puzzling enzyme commonly referred to as the "distances paradox", which arises from the existence of a large 8-angstrom distance between the two reactive atoms in the reaction catalyzed by this enzyme: a Zn-bound cysteine sulphur atom from a peptidic substrate and the farnesyldiphosphate (FPP) carbon 1. This distance must be overcome for the reaction to occur. In this study, the two possible alternatives were evaluated by combining molecular mechanics (AMBER) and quantum chemical calculations (B3LYP). Basically, our results have shown that an activation of the Zn-bound cysteine thiolate with subsequent displacement from the zinc coordination sphere towards the FPP carbon 1 is not a realistic hypothesis of overcoming the large distance reported in the crystallographic structures of the ternary complexes between the two reactive atoms, but that a rotation involving the FPP molecule can bring the two atoms closer with moderate energetic cost, coherent with previous experimental data. This conclusion opens the door to an understanding of the chemical step in the farnesylation reaction. Proteins 2007;66:205-218. (c) 2006 Wiley-Liss, Inc.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14