Controlling the dissociation of ligands from the adenosine A2A receptor through modulation of salt bridge strength

DOI: 10.1021/acs.jmedchem.6b00653

Authors: Elena Segala (Heptares Therapeutics Ltd) , Dong Guo (Leiden University) , Robert K. Y. Cheng (Heptares Therapeutics Ltd) , Andrea Bortolato (Heptares Therapeutics Ltd) , Francesca Deflorian (Heptares Therapeutics Ltd) , Andrew S. Doré (Heptares Therapeutics Ltd) , James C. Errey (Heptares Therapeutics Ltd) , Laura H. Heitman (Leiden University) , Adriaan P. Ijzerman (Leiden University) , Fiona H. Marshall (Heptares Therapeutics Ltd) , Robert M. Cooke (Heptares Therapeutics Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 59 , PAGES 6470 - 6479

State: Published (Approved)
Published: July 2016

Abstract: The association and dissociation kinetics of ligands binding to proteins vary considerably, but the mechanisms behind this variability are poorly understood, limiting their utilization for drug discovery. This is particularly so for G protein-coupled receptors (GPCRs) where high resolution structural information is only beginning to emerge. Engineering the human A2A adenosine receptor has allowed structures to be solved in complex with the reference compound ZM241385 and four related ligands at high resolution. Differences between the structures are limited, with the most pronounced being the interaction of each ligand with a salt bridge on the extracellular side of the receptor. Mutagenesis experiments confirm the role of this salt bridge in controlling the dissociation kinetics of the ligands from the receptor, while molecular dynamics simulations demonstrate the ability of ligands to modulate salt bridge stability. These results shed light on a structural determinant of ligand dissociation kinetics and identify a means by which this property may be optimized.

Journal Keywords: Salts; Dissociation; Ligands; Kinetics; Receptors

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 17/11/2016 15:28

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)