5IUA

Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with compound 12b at 2.2A resolution

Summary for 5IUA

• Entry DOI: 10.2210/pdb5iua/pdb
• Related: 5IU4 5IU7 5IU8
• Descriptor: Adenosine receptor A2a,Soluble cytochrome b562,Adenosine receptor A2a, SODIUM ION, 2-(furan-2-yl)-N~5~-[3-(4-phenylpiperazin-1-yl)propyl][1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine, ... (7 entities in total)
• Functional Keywords: g-protein-coupled receptor, integral membrane protein, chimera, thermostabilizing mutations, membrane protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P29274
• Total number of polymer chains: 1
• Total formula weight: 57639.99

Authors

Segala, E.,Guo, D.,Cheng, R.K.Y.,Bortolato, A.,Deflorian, F.,Dore, A.S.,Errey, J.C.,Heitman, L.H.,Ijzerman, A.P.,Marshall, F.H.,Cooke, R.M. (deposition date: 2016-03-17, release date: 2016-06-29, Last modification date: 2024-10-16)

Primary citation

Segala, E.,Guo, D.,Cheng, R.K.,Bortolato, A.,Deflorian, F.,Dore, A.S.,Errey, J.C.,Heitman, L.H.,IJzerman, A.P.,Marshall, F.H.,Cooke, R.M.
Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength.
J.Med.Chem., 59:6470-6479, 2016

PubMed 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.

PubMed: 27312113
DOI: 10.1021/acs.jmedchem.6b00653

Experimental method

X-RAY DIFFRACTION (2.2 Å)