Structure, Dynamics and Activation Mechanisms of Chemokine Receptors
This biological project is composed of investigators from the University of California, San Diego, University of California, Los Angeles, and Case Western Reserve University and is partnered with the PSI Membrane Center - GPCR Network at The Scripps Research Institute.
- University of California, San Diego
- University of California, Los Angeles
- Case Western Reserve University
Chemokine receptors are a class of GPCRs best known for their pivotal role in immune surveillance, where they control the migration and activation of leukocytes in an effort to detect and resolve physiological abnormalities such as cancer and infection. However, inappropriate expression or regulation of these receptors is associated with an extraordinary number of pathologies including inflammatory diseases, cancer and AIDS. Thus, in collaboration with the Center for Membrane Protein Structure Determination (CMPD) GPCR Network, our primary goal is to determine crystallographic structures of chemokine receptors and complexes that can aid drug discovery efforts. To gain insight into the dynamic aspects of receptor function, the crystallographic work will be complemented with biophysical studies. Radiolytic footprinting will be developed and applied to map the binding interfaces between chemokines and receptors and to determine information on activation mechanisms. Site Directed Spin Labeling with Electron Paramagnetic Resonance will be used to characterize the conformational changes associated with ligand binding. The experimental work will be tightly integrated with computational modeling approaches in order to interpret the processes of ligand binding and activation in a three-dimensional context, to predict improved drugs, and to guide experiment design. Structure-inspired biological experiments to probe the relationship between structure and function will also be conducted.