Structure of Human Cytochrome P450 2D6 Solved by GlaxoSmithKline with the Use of Fluidigm Technology
Friday March 17, 2:00 pm ET
Latest Discovery One of over 30 Structures Involving TOPAZ System in Previous Twelve Months
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--March 17, 2006--The TOPAZ® system for protein crystallization was instrumental in helping GlaxoSmithKline (GSK) solve the structure of cytochrome P450 2D6 -- an enzyme important in the metabolism of a wide variety of drugs. TOPAZ crystallization chips were used to identify positive conditions for crystallization and subsequently to grow P450 2D6 crystals sufficiently large and well ordered for structural analysis. The research was conducted by the GSK Discovery Research Group in Harlow, UK, and the findings are presented in the March 17 issue of the Journal of Biological Chemistry. This structure is one of over 30 generated by customers using the TOPAZ system in the past twelve months.
For this protein target, conventional microplate crystallization trials failed to yield crystals suitable for an X-ray crystal structure determination, according to Paul Rowland, Investigator, Structural Sciences at GSK. Consequently, the team turned to TOPAZ preparative chips to further explore crystallisation conditions and to scale up those which appeared promising. In the paper Rowland et al. describe the procedure whereby crystals were grown and harvested from the TOPAZ chips and then used to solve the protein structure.
"The success of this research bodes well for a chip-based approach, from initial screening of conditions through growth of diffraction-quality crystals," said Drake Eggleston, Vice President, Computational, Analytical & Structural Sciences. "The approach provides a number of potential advantages because the TOPAZ system is more efficient than microplates for discovery screening in terms of sample consumption and image analysis."
The P450 2D6 structure is a milestone in ongoing work to determine the structures of various bound substrates and inhibitors related to ligand recognition and specificity in human cytochrome systems. A relatively large number of genetic polymorphisms have been described for 2D6, some of which are markers for rapid, or conversely, very poor metabolism. A deeper understanding of these polymorphisms as facilitated by 3-dimensional structural considerations may lead to safer, more efficacious drugs. The publication of the P450 2D6 structure attests to the value of a long-standing collaboration between GSK and Fluidigm to integrate TOPAZ technology into the drug discovery process.
About Fluidigm
Fluidigm develops and distributes systems based on the unique properties of integrated fluidic circuits (IFCs) to manipulate fluids on a micro- and nano-volume scale. The company's vision is to create and to lead a new industry in which IFCs bring efficiencies inconceivable today to life science and allied fields. In 2003 the Company introduced the TOPAZ® system, which speeds the discovery of protein structure, an essential step in rational drug design. Currently, the Company is rolling out the BioMark(TM) system, instrumentation and IFCs for high-throughput real-time QPCR and detection of a target sequences in a high background of similar sequences. Applications in the development pipeline include the following: miniaturized, high-throughput immunoassays, rapid synthesis of radio-labeled imaging probes, and preparation of nucleic acids for analysis. Based in South San Francisco, California, the Company is privately held and backed by premier investors: Versant Ventures, Euclid SR Partners, InterWest Partners, Lehman Brothers Healthcare Fund, Bruce Burrows, the Singapore EDB, Lilly BioVentures, the Invus Group, GE Equity, SightLine Partners, and Alloy Ventures. |
