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

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

Eric M Rosenberg Jr, Reed E S Harrison, Lun Kelvin Tsou, Natalie Drucker, Brock Humphries, Deepa Rajasekaran, Kathryn E Luker, Chien-Huang Wu, Jen-Shin Song, Chuan-Jen Wang, James W Murphy, Yung-Chi Cheng, etc.

Cell Chem Biol. 2019 May 16;26(5):662-673.e7.

PMID: 30827936

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249393	CXCR4 Antagonist III			Price

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