Structural Biology of Chemokines/Receptors and Their Role in Disease
Skaggs School of Pharmacy and Pharmaceutical Sciences
Department of Pharmacology
Dr. Handel's laboratory takes a multidisciplinary approach including cell and molecular biology, biochemistry, biophysics and structural biology to study 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 diseases, atherosclerosis, cancer, and HIV. A major area of study includes determining the structure of chemokine receptors in complex with their natural protein ligands (e.g. Qin et al. Science, 2015) and small molecule antagonists (e.g. Zheng et al. Nature, 2016). This work is challenging because chemokine receptors are membrane-imbedded G protein-coupled receptors (GPCRs) which are difficult to express, purify and crystallize. GPCRs in general and chemokine receptors in particular are important therapeutic targets and this work should contribute significantly to drug discovery. In fact, the work by Zheng et al. will form the basis for a new drug discovery initiative targeting the chemokine receptor, CCR2. The laboratory also studies the structural and dynamic basic for receptor activation (e.g. Wescott et al., PNAS, 2016), again to facilitate drug discovery.
Education: B.S. in Chemistry (1980) Bucknell; Ph.D. in Chemistry (1989) Caltech. Postdoc in Biophysics (1989-92) Dupont Merck Pharmaceuticals.
Awards and Honors: PSI:Biology UO1 Grant; Caltech McKoy Award for Excellence in Graduate Research (1988); Long Term Incentive Award at DuPont Merck (1993); Highest Relative Performance Rating at Dupont Merck (1993); NSF Young Investigator Award (1994); Pew Scholars Award (1995); Hellman Fellows Award (1996); Berkeley Research & Teaching Award (2000). Chair of Gordon Research Conference on Chemotactic Cytokines (2014-1016); Nauta Chair Award, Vrije Universiteit, Amsterdam 2018; Chair, Division for Molecular Pharmacology, The American Society for Pharmacology and Experimental Therapeutics (ASPET, 2018).
Leadership Experience: UC San Diego: Chair, Division of Pharmaceutical Sciences, SSPPS (2016-present), Chair Biomedical Sciences Program (2010-2013), Vice Chair Biomedical Sciences Program (2008-2010), SSPPS Faculty Chair (2008-2010), Chair Biomedical Sciences Admissions Committee (2006-2009), Health Sciences Research Council (6/2005-present), Health Sciences Faculty Council (6/2007-present). Co-Chair, Molecular Biophysics Program (Fall 2014-2018). Co-Chair Molecular Pharmacology Training area of BMS program, Co-Director Pharmacological Sciences Training Grant Program.
- Pharmaceutical Biochemistry (SSPPS 223, Course Director)
- Drugs and Disease (Biom/Phar 255A, Course Co-Director)
- Contemporary Topics in Pharmacology (SSPPS 218B)
- Careers in Biomedical Sciences (Biom/Phar 234, Course Co-Director)
- Molecules to Man (Biom 200)
- Scientific Research Ethics (BIOM 219)
- Pharmaceutical Sciences and Drug Development (SPPS 263A)
- Cardiovascular System I: Facilitator in an autonomic nervous system small group problem based learning activity for medical and pharmacy students
- Renal System I: Facilitator in a pharmacokinetics small group problem based learning activity for medical and pharmacy students
- Solved the first structure of a chemokine receptor, CXCR4, with a chemokine
- Defined for the first time, the activation pathway from chemokine to G protein through the transmembrane helices of chemokine receptor, CXCR4
- Determined the structure of CCR2 simultaneously bound to an orthosteric and an allosteric antagonist and defined novel mechanisms for inhibiting the receptor.
- Determine the structure of CCR5 in complex with chemokine, and showed how HIV GP120 likely mimics chemokine interactions with receptors as a mechanism for HIV to enter cells.
- Discovered several novel mechanisms of receptor antagonism based on modified chemokines. Developed novel methods to select for high affinity chemokine antagonists.
- Discovered novel mechanisms by which chemokines contribute to cancer, and the potential of small molecule inhibitors for CLL.
- Qin L et al. (2015) Structural Biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science. 347:1117-22.
- Gustavsson M et al. (2016) Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Communications 8:14135
- Zheng Y et al. (2016) Structure of CC Chemokine Receptor 2 with Ortho- and Allosteric Antagonists. Nature. 540, 458-461
- Wescott MP et al. (2016) Signal Transmission through the CXC Chemokine Receptor 4 (CXCR4) Transmembrane Helices. Proc. Natl. Acad. Sci. 113:9928-33.
- Zheng Y et. al., (2017) Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. Immunity 46(6):1005-1017