Mapping the allosteric sites of the A 2A adenosine receptor

The A adenosine receptor (A AR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neurodegeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor confor...

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Bibliographic Details
Published in:Chemical biology & drug design 2018-01, Vol.91 (1), p.5-16
Main Authors: Caliman, Alisha D, Miao, Yinglong, McCammon, James A
Format: Article
Language:English
Subjects:
Adenosine A2 Receptor Agonists - chemistry
Adenosine A2 Receptor Agonists - metabolism
Adenosine A2 Receptor Antagonists - chemistry
Adenosine A2 Receptor Antagonists - metabolism
Algorithms
Allosteric Site
Binding Sites
Humans
Molecular Dynamics Simulation
Protein Domains
Protein Interaction Maps
Protein Structure, Tertiary
Receptor, Adenosine A2A - chemistry
Receptor, Adenosine A2A - metabolism
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Summary:The A adenosine receptor (A AR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neurodegeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID: 3QAK) and antagonist-bound (PDB ID: 3EML) X-ray structures. This analysis revealed four distinct conformers of the A AR: the active, intermediate 1, intermediate 2, and inactive. In this study, we apply the fragment-based mapping algorithm, FTMap, on these receptor conformations to uncover five non-orthosteric sites on the A AR. Two sites that are identified in the active conformation are located in the intracellular region of the transmembrane helices (TM) 3/TM4 and the G protein-binding site in the intracellular region between TM2/TM3/TM6/TM7. Three sites are identified in the intermediate 1 and intermediate 2 conformations, annexing a site in the lipid interface of TM5/TM6. Five sites are identified in the inactive conformation, comprising a site in the intracellular region of TM1/TM7 and in the extracellular region of TM3/TM4 of the A AR. We postulate that these sites on the A AR be screened for allosteric modulators for the treatment of inflammatory and neurological diseases.
ISSN:1747-0277
1747-0285
DOI:10.1111/cbdd.13053