Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

CXCR4, a member of the family of chemokine-activated G protein-coupled receptors, is widely expressed in immune response cells. It is involved in both cancer development and progression as well as viral infection, notably by HIV-1. A variety of methods, including structural information, have suggested the receptor may exist as a dimer or oligomer. However, the mechanistic details surrounding receptor oligomerization and its potential dynamic regulation remain unclear. Using both biochemical and biophysical means we confirm that CXCR4 can exist as a mixture of monomers, dimers and higher-order oligomers in cell membranes and show that oligomeric structure becomes more complex as receptor expression levels increase. Mutations of CXCR4 residues located at a putative dimerization interface result in monomerization of the receptor. Additionally, binding of the CXCR4 antagonist IT1t— a small, drug-like isothiourea derivative — rapidly destabilizes the oligomeric structure, while AMD3100, another well-characterized CXCR4 antagonist, does not. Although a mutation that regulates constitutive activity of CXCR4 also results in monomerization of the receptor, binding of IT1t to this variant promotes receptor dimerization. These results provide novel insights into the basal organization of CXCR4 and how antagonist ligands of different chemotypes differentially regulate its oligomerization state

Integrated Molecular and Cellular Biophysics

This book integrates concepts and methods from physics, biology, biochemistry and physical chemistry into a standalone, unitary text of biophysics that aims to provide a quantitative description of structures and processes occurring in living matter. The book introduces graduate physics students and physicists interested in biophysics research to 'classical' as well as emerging areas of biophysics. The advanced undergraduate physics students and the life scientists are also invited to join in, by building on their knowledge of basic physics. Essential notions of biochemistry and biology are introduced, as necessary, throughout the book, while the reader's familiarity with basic knowledge of physics is assumed. Topics covered include interactions between biological molecules, physical chemistry of phospholipids association into bilayer membranes, DNA and protein structure and folding, passive and active electrical properties of the cell membrane, classical as well as fractal aspects of reaction kinetics and diffusion in biological systems, structural and functional aspects of molecular machines (including channels, ion pumps, and light-harvesting antenna), as well as fundamental aspects of proteins association in solutions and in living cells

Dielectric relaxation in biological systems: physical principles, methods, and applications

This title covers the theoretical basis and practical aspects of the study of dielectric properties of biological systems, such as water, electrolyte and polyelectrolytes, solutions of biological macromolecules, cells suspensions and cellular systems

Proteins in Solutions and Natural Membranes

In the first part of the chapter, dielectric spectroscopy studies of globular proteins in aqueous solutions in native and denatured states are reviewed. Here we discuss the mechanisms of two major dielectric relaxation processes (γ- and β-dispersions) and one minor process (δ-dispersion) observed in the diluted globular protein solutions. Effects of protein concentration, temperature, pH, and denaturants were also summarized. The second part of the chapter presents the dielectric properties of proteins in natural membrane fragments and living cells membrane. Ferroelectric behavior was observed for the first time for the package of bacteriorhodopsin membrane fragments oriented in the electric field. Here, a discussion is also presented about progress and problems related to the observation of proteins in living cells using dielectric spectroscop