Structure, Dynamics, and Mechanism of Chemokines and their G-protein Coupled Receptors

Chemokines are secreted proteins that activate G-protein coupled receptors to mediate the migration of specific cells to the appropriate anatomical locations in response to physiological signals (homeostasis) and pathophysiological insults (immunity). Some of the >45 human chemokines have roles in embryonic development or homeostasis, while most cause inflammation, autoimmune diseases, or cancer metastasis. We have studied and determined the structures of CXCL12 in various oligomeric forms, CXCL12 bound to heparin, vMIPII (vCCL2), CXCL13, murine MIP-2, and a fifth family in zebrafish (CXL1).

The ~20 chemokine receptors belong to a small subfamily of the 800 GPCR family, which constitutes the largest protein family targeted by FDA approved drugs. Binding of chemokines to specific GPCRs triggers a cascade of dynamic motions that eventually mediates the exchange of GDP for GTP on the intracellular Gα protein and its disassociation from both the GPCR and its subunits Gβγ. We have used molecular dynamics to define these motions that occur on a constitutively active mutant chemokine receptor and are currently using crystallography and cryo-EM to determine the structure of an antagonist-receptor complex and chemokine-receptor complex, respectively.