Biological membranes are needed by all life forms. These lipid bilayers separate the inside and outside of the cell and, in higher organisms, provide the separation between internal compartments. As such, they are the site for processes of that provide recognition and communication and provide the home to a host of proteins that mediate signaling, catalysis and the generation and transduction of energy and the import and export of molecules. Despite this central role in life, membranes and membrane proteins have often been difficult to study using the normal tools of biochemistry and molecular biology. Membrane proteins display loss or altered activity when removed from their native lipid environment. Likewise, revealing the fundamental molecular recognition events involved in forming complex multi-component architectures at the membrane surface requires new methodologies. Nanodiscs, self-assembled nanoscale lipid bilayers solubilized by an amphipathic scaffold protein discovered in our laboratory, have served to enable new discoveries in these arenas. Under support from this award, we will further develop the Nanodisc system to provide novel biochemical and biophysical paths to the realization of the mechanisms involved in catalysis, signaling and molecular recognition. Complex macromolecular assemblies under investigation include those involved in blood coagulation, xenobiotic and hormone metabolism and cell transformation/migration.
Nanodiscs, nanometer scale lipid bilayers encircled by two amphipathic protein belts discovered in our laboratory, has proven to be enabling for investigations involving membranes and membrane proteins. This award will support further development of the Nanodisc platform and its broad application to the field of membrane protein enzymology and biological signaling.
| Mak, Piotr J; Duggal, Ruchia; Denisov, Ilia G et al. (2018) Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone. J Am Chem Soc 140:7324-7331 |
| Mak, Piotr J; Denisov, Ilia G (2018) Spectroscopic studies of the cytochrome P450 reaction mechanisms. Biochim Biophys Acta Proteins Proteom 1866:178-204 |
| Denisov, Ilia G; Baylon, Javier L; Grinkova, Yelena V et al. (2018) Drug-Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4. Biochemistry 57:805-816 |
| Gregory, Michael C; Mak, Piotr J; Khatri, Yogan et al. (2018) Human P450 CYP17A1: Control of Substrate Preference by Asparagine 202. Biochemistry 57:764-771 |
| DiChiara, Thomas; DiNunno, Nadia; Clark, Jeffrey et al. (2017) Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station. Yale J Biol Med 90:45-61 |
| Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G et al. (2017) Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chem Biol 24:1259-1275.e6 |
| Denisov, Ilia G; Sligar, Stephen G (2017) Nanodiscs in Membrane Biochemistry and Biophysics. Chem Rev 117:4669-4713 |
| Gregory, Michael C; McLean, Mark A; Sligar, Stephen G (2017) Interaction of KRas4b with anionic membranes: A special role for PIP2. Biochem Biophys Res Commun 487:351-355 |
| Duggal, Ruchia; Liu, Yilin; Gregory, Michael C et al. (2016) Evidence that cytochrome b5 acts as a redox donor in CYP17A1 mediated androgen synthesis. Biochem Biophys Res Commun 477:202-8 |
| Her, Cheng; Filoti, Dana I; McLean, Mark A et al. (2016) The Charge Properties of Phospholipid Nanodiscs. Biophys J 111:989-98 |
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