Chemokines are small signaling proteins that control cell migration through the formation of extracellular concentration gradients. Binding of chemokines to chemokine receptors activates intracellular signaling pathways, leading to chemotaxis of leukocytes during an inflammatory response. Chemokines and their receptors are thereby a crucial part of the immune system and regulate a number of other physiological functions including development and angiogenesis. Most chemokine receptors belong to the large family of G-protein coupled receptors that are ubiquitous in human cells and constitute ~40% of current drug targets. CXCR7 (also known as atypical chemokine receptor 3, ACKR3) is an atypical (not G-protein coupled) chemokine receptor that binds the chemokines SDF-1 (shared with CXCR4) and I-TAC (shared with CXCR3). This binding triggers β-arrestin dependent signaling pathways and regulates signaling of other receptors by controlling the extracellular chemokine concentration. CXCR7 expression is up-regulated in different forms of cancer and inhibiting CXCR7 with siRNA or a small molecule CXCR7 antagonist can reduce tumor size and slow down cancer progression. These findings make CXCR7 a therapeutic target and an antagonist of CXCR7 is currently tested in preclinical trials to treat glioblastoma multiforme.

The aim of this study is to understand the mechanism of chemokine binding and signal transduction for CXCR7. This is done by determining a high resolution structure of CXCR7 in complex with SDF-1 and a small molecule antagonist using x-ray crystallography in combination with other complimentary methods. To date, the conditions for production of large amounts of stable, functional CXCR7 protein have been optimized and lipid cubic phase crystals have been obtained of CXCR7 in complex with a high affinity mutant of SDF-1. and key sites of interaction between the receptor and chemokine have been identified. Currently, crystallization conditions are being optimized to produce crystals large enough to enable structure determination. High resolution structures of CXCR7 in complex with SDF-1 and antagonists could facilitate the development of new therapeutics targeting CXCR7 with higher affinity and specificity. A structure of CXCR7 in complex with SDF-1 could also reveal the molecular details of chemokine binding, and the structural differences between the atypical CXCR7 and other chemokine receptors that lead to triggering of different signaling pathways upon chemokine binding.

Citation Format: Martin Gustavsson, Yi Zheng, Ling Qin, Lauren G. Holden, Irina Kufareva, Tracy M. Handel. Towards an understanding of the structural basis of CXCR7 ligand binding and signaling. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A168.