title: Detection of farnesyltransferase interface hot spots through computational alanine scanning mutagenesis.
abstract: In this study, we present a detailed characterization of the full α/β interface in the farnesyltransferase (FTase) enzyme, an important target in drug design efforts. This characterization is presented in terms of hot spots, warm spots, and null spots and is based on the application of an improved variation of the computational alanine scanning mutagenesis methodology, complemented with extensive solvent-accessible surface area and interfacial hydrogen-bonding analysis. A total of 130 interface amino acid residues were considered in this analysis, a number that represents 16.0% of the total of 814 amino acid residues in the full enzyme. Globally, the results provide important clues on the most important structural and energetic determinants for dimer formation, suggesting several key targets at the subunit interface for the development of new molecules that aim to inhibit FTase activity through blocking the formation of the fully active FTase dimer, yielding useful indications for future drug design efforts.
authors: REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.
authors: Marta A S
authors: MA
authors: Perez
authors: Sérgio F
authors: SF
authors: Sousa
authors: Eduardo F T
authors: EF
authors: Oliveira
authors: Pedro A
authors: PA
authors: Fernandes
authors: Maria J
authors: MJ
authors: Ramos
mesh_terms: D000409:Alanine / Q000737:chemistry*; D015195:Drug Design; D051231:Farnesyltranstransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D012997:Solvents; D051231:Farnesyltranstransferase; D000409:Alanine