318G Roger Adams Laboratory
600 S Mathews
Urbana, IL 81801
Office: (217) 300-1454
Mail to: Department of Biochemistry
419 RAL, Box B4
600 S Mathews
Urbana, IL 61801
Assistant Professor of Biochemistry
Professor of Biophysics and Quantitative Biology
Computational Biology, Protein Structure, Receptor Biochemistry
B.Sc. 2002 University of Adelaide, Australia
B.Sc.(Hons) 2003 University of Adelaide, Australia
Ph.D. 2008 Harvard University, Boston
Postdoc. 2009-2014 University of Washington, Seattle
Directed Evolution, Membrane Protein Structure and Function, Molecular Recognition, Neurotransmitters, Taste, G Protein-Coupled Receptors, HIV-1
Many proteins undergo large conformational changes as they carry out their functions. This includes receptors that shift between active and resting states, transporters that alternate access to a substrate binding site from one side of the membrane to the other, and proteins that bring two membrane together during membrane fusion. To understand protein behavior, biochemists frequently introduce mutations, perhaps to lock a receptor in an active state, or change the energy barriers between outwards and inwards facing states of a transporter. A detailed understanding of how amino acid sequence informs protein biophysical behavior can help determine protein mechanism and assist in engineering proteins with altered properties. But where should one begin? What mutations will increase protein activity? What mutations will shift the equilibria between protein conformational states?
The Procko lab has developed 'Big Data' tools for deep mutational scanning of transmembrane proteins in mammalian cells. By combining in vitro evolution with deep sequencing, it becomes possible to characterize the phenotypes of thousands of receptor mutants in a single experiment, and a comprehensive sequence-fitness landscape of a protein can be experimentally determined. Mutations can then be identified that alter protein activity, with a particular focus on finding mutations that drive proteins into specific conformations. We are currently focused on three membrane protein systems: neurotransmitter transporters associated with psychiatric disease, G protein-coupled receptors in the immune and nervous systems (including receptors for taste, chemokines and HIV-1 entry), and the HIV-1 envelope fusion protein.
Park J, et al. (2019) Structural architecture of a dimeric class C GPCR based on co-trafficking of sweet taste receptor subunits. J Biol Chem doi: 10.1074/jbc.RA118.006173
Heredia JD, et al. (2018) Mapping Interaction Sites on Human Chemokine Receptors by Deep Mutational Scanning. J Immunol 200(11):3825-3839.
Kim EC, et al. (2018) Reduced axonal surface expression and phosphoinositide sensitivity in Kv7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy. Neurobiology of disease 118:76-93.
Berger S, et al. (2016) Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer. Elife 5:e20352.
Harris DT, et al. (2016) Deep Mutational Scans as a Guide to Engineering High Affinity T Cell Receptor Interactions with Peptide-bound Major Histocompatibility Complex. J Biol Chem 291(47):24566-24578.
Harris DT, et al. (2016) An Engineered Switch in T Cell Receptor Specificity Leads to an Unusual but Functional Binding Geometry. Structure 24(7):1142-54.
Procko E,* Berguig GY,* et al. (2014) A computationally designed inhibitor of an Epstein-Barr viral BCL-2 protein induces apoptosis in infected cells. Cell 157(7):1644-56.
Procko E, et al. (2013) Computational design of a protein-based enzyme inhibitor. J Mol Biol 425(18):3563-75.
Geibel S,* Procko E,* Hultgren SJ, Baker D, Waksman G. (2013) Structural and energetic basis of folded-protein transport by the FimD usher. Nature 496(7444):243-6.