DNA nanotube liquid crystals for NMR structure determination
NMR is currently used in support of structure-based drug design, in which the 3-D structure of a drug target interacting with small molecules is used to guide drug discovery. NMR is also used upstream in the drug discovery process to determine how a new drug will bind with its target molecule, optimizing leads, and as a component of the screening process. NMR spectroscopy sales are estimated at $350-400 million annually. Demand for drug discovery applications is estimated to grow at an average of 10% per year.
Innovations and Advantages
Scientists at the Harvard Medical School and the Dana-Farber Cancer institute have discovered how to make DNA nanotubes of a uniform length that will self-assemble into liquid crystals. A solution comprising liquid crystalline DNA nanotubes is resistant to detergent and enables liquid-crystal NMR spectroscopy of membrane proteins solubilized in detergent. The DNA nanotube liquid crystans can be manufactured on a large-scale to achieve economies of scale, and then sold in aliquots to solution NMR spectroscopists across the world interested in solving the structure of clinically-relevant membrane proteins that can be the focus of structure-based drug design.
With current NMR technology it is quite difficult to analyze membrane proteins because membrane-embedded proteins are not readily amenable to existing crystallization methods. Solution NMR can be used to obtain structural information without the need for crystallization – but this requires that proteins are solubilized in detergents. This limits the practicality of this approach to relatively small membrane associated proteins. It is believed that ~30% of all expressed polypeptides are membrane associated, and G-protein-coupled receptors (GPCRs) and ion channels, which are integral membrane proteins, comprise more thant 50% of human drug targets.
This invention makes possible the accurate measurement of residual dipolar couplings (RDCs) for a wide array of detergent solubilized proteins. This will facilitate the de novo NMR structure determination of large membrane proteins that cannot be determined using current techniques. This could potentially extend the size limit for solution-NMR based structure determination of membrane proteins – making it possible to determine the structures of larger membrane proteins that are good drug targets.
Intellectual Property Status: Issued U.S. patent nos.: 7,951,596
Chou, James J.
Douglas, Shawn M.
Shih, Willilam M.
For further information, please contact:
Grant Zimmermann, Director of Business Development
Reference Harvard Case #2905