NUCLEIC ACID NANOTUBE LIQUID CRYSTALS AND USE FOR NMR STRUCTURE DETERMINATION OF DETERGENT-SOLUBILIZED MEMBRANE PROTEINS

Dana-Farber Cancer Institute
posted on 09/16/2011

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Scientists at the Harvard Medical School and the Dana-Farber Cancer institute have 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 crystals can be manufactures 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.

Current problems with the state of NMR for membrane proteins:
? 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 (see market indicators page).

How this invention will solve this problem:
? 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.

How it would be sold as a product:
? Sold as a consumable solution that everyone running an NMR spec would use to determine membrane structure

Use of solution NMR in Drug Discovery
? 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

The increasing use of NMR:
? 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