Tracy Handel, Ph.D.
Tracy Handel
Distinguished Professor of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences
Tracy Handel, Ph.D.
Distinguished Professor of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences
Research Interests
Our research is focused on the structure and function of chemokines and chemokine receptors. These proteins control the migration of cells during development, immune surveillance, and inflammation. However, inappropriate regulation of chemokines/receptors is also associated with numerous diseases including inflammatory diseas¬es, atherosclerosis, cancer, and HIV. We use cryo-EM and crystallography to determine structures of receptors in complex with ligands (chemokine and small molecule agonists and antagonists), and intracellular signaling partners (G proteins, GRKs and arrestins). These studies are complimented by biophysical studies such as single molecule fluorescence, and functional studies in cells. We also seek to ident ify the network of interacting proteins involved in signaling downstream of the receptors and receptor trafficking. Protein-protein interactions are identified by proximity labeling mass spectrometry (APEX) and the resultsintegrated into computational network models with collaborator Irina Kufareva. In a more recent collaboration with Pharmacology Chair, Silvio Gutkind, we are investigating whether one can alter the leukocyte composition of the tumor immune microenvironment (TIME) in a manner that increases the effectiveness of checkpoint inhibitors by exploiting specific chemokine receptors. This work involves studies of receptor pharmacology, biochemistry including strategies for nanoparticle delivery of chemokines to the TIME, and in vivo studies.
Selected Publications
Stephens BS, Ngo T, Kufareva I, Handel TM. (2020) Functional anatomy of the full length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis. Science Signaling, 3(640):eaay5024. doi: 10.1126/scisignal.aay5024
Zheng Y, Han GW, Abagyan R, Wu B, Stevens RC, Cherezov V, Kufareva I, Handel TM. (2017) Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. Immunity. 46:1005-1017.
Gustavsson M, Wang L, van Gils N, Stephens BS, Zhang P, Schall TJ, Yang S, Abagyan R, Chance MR, Kufareva I, Handel TM. (2017) Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Communications. 8:14135.
Zheng Y, Qin L, Ortiz Zacarías NV, de Vries H, Han GW, Martin Gustavsson M, Dabros M, Zhao C, Cherney R, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM. (2016) Structure of CC Chemokine Receptor 2 with Ortho- and Allosteric Antagonists. Nature. 40:458-461.
Wescott MP, Kufareva I, Paes C, Goodman JR, Thaker Y, Puffer BA, Berdougo E, Rucker JR, Handel TM and Doranz B. (2016) Signal Transmission through the CXC Chemokine Receptor 4 (CXCR4) Transmembrane Helices. Proc. Natl. Acad. Sci. 113:9928-33.
Qin L, Kufareva I, Holden LG, Wang C, Zheng Y, Zhao C, Fenalti G, Wu H, Han GW, Cherezov V, Abagyan R, Stevens RC, Handel TM (2015) Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science. 2015 347:1117-22. Epub 2015 Jan 22.