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Cell Chem Biol. 2019 May 16;26(5):662-673.e7. doi: 10.1016/j.chembiol.2019.01.012. Epub 2019 Feb 28.

Characterization, Dynamics, and Mechanism of CXCR4 Antagonists on a Constitutively Active Mutant.

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Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA.
Department of Bioengineering, Bourns College of Engineering, University of California, Riverside, CA 92507, USA.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 35053, Taiwan, R.O.C.
University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI 48109, USA.
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:


The G protein-coupled receptor (GPCR) CXCR4 is a co-receptor for HIV and is involved in cancers and autoimmune diseases. We characterized five purine or quinazoline core polyamine pharmacophores used for targeting CXCR4 dysregulation in diseases. All were neutral antagonists for wild-type CXCR4 and two were biased antagonists with effects on β-arrestin-2 only at high concentrations. These compounds displayed various activities for a constitutively active mutant (CAM). We use the IT1t-CXCR4 crystal structure and molecular dynamics (MD) simulations to develop two hypotheses for the activation of the N1193.35A CAM. The N1193.35A mutation facilitates increased coupling of TM helices III and VI. IT1t deactivates the CAM by disrupting the coupling between TM helices III and VI, mediated primarily by residue F872.53. Mutants of F872.53 in N1193.35A CXCR4 precluded constitutive signaling and prevented inverse agonism. This work characterizes CXCR4 ligands and provides a mechanism for N1193.35A constitutive activation.


CXCL12; CXCR4; G protein-coupled receptor (GPCR); constitutively active mutant (CAM); molecular dynamics (MD); small molecule ligands

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