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PIP Binding



Phosphorylated phosphstidylinositols (PIPs) are a class of molecules   implicated in membrane trafficking and lipid signaling.While considerable work   has been done in understanding how PIPs participate in various inter- and intracellular processes, the interaction of PIPs with membrane-bound proteins remains poorly understood. We are developing ssNMR methods to examine PIP binding to AKT2, a PI(3,4)P2 and PIP3 kinase associated with various diseases, including ovarian cancer and diabedes.

A common challenge for studying enzyme-substrate complexes is being able to detect bound states with short lifetimes or bound states in which the ligand-protein interaction is weak.






Membrane Proteins

Membrane proteins are a ubiquitous and understudied portion of the human proteome. Due to challenges of studying them in their native lipid environment, much of what we know about their structure and function comes from samples in detergent or bilayer mimetics and crystal structures. While these studies have proven to be a useful starting point for studying them, they are just that.  si we know that the exact composition of the membrane can have large effects on the activity of membrane proteins. Therefore, we are developing methods to investigate membrane proteins in native or near-native environments. This includes assignment and 3D-structure determination, as well as site-specific protein lipid interactions. Strategies we plan to employ are the use of nanodisks.



NMR Method Development

We seek to apply the power of 1H-detected ssNMR to growing numbers of areas in ssNMR. Due to the fact 1H’s gyromagnetic ratio is 4 times that of 13C, experiments detecting 1H are more sensitive and therefore faster. While 1H detection is increasing well developed in terms of chemical shift assignments, there is still a wide array of areas where it has not yet been deployed. In particular, we are interested on using ultrafast MAS with 1H detection to gain structural insight without deuterated samples. We are developing new pulse sequences to determine intermolecular distances both within a protein and intermolecularly, as well as study dynamics at many timescales. We have a MAS probe which can spin at 40 kHz and another which spins at 100 kHz is on the way.

In addition to 1H detected methods, we will use 31P detected methods. 31P is spin 1/2, 100% abundant, and relatively high gamma (17.235 MHz/T). It has good lineshape and sensetivity, a wide chemical shift range, and a large dipolar coupling range (~ 8 A). In addition, we expect to be able to filter out the lipid phosphate signal to obtain spectra with good signal-to-noise of specific phosphates we are interested in.

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Chemistry and Chemical Biology
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