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Predicted structures of agonist and antagonist bound complexes of adenosine A 3 receptor
Author(s) -
Kim SooKyung,
Riley Lindsay,
Abrol Ravinder,
Jacobson Kenneth A.,
Goddard William A.
Publication year - 2011
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.23012
Subject(s) - g protein coupled receptor , agonist , chemistry , docking (animal) , adenosine receptor , receptor , ligand (biochemistry) , helix (gastropod) , binding pocket , stereochemistry , adenosine , antagonist , binding site , biophysics , biochemistry , biology , medicine , ecology , nursing , snail
We used the GEnSeMBLE Monte Carlo method to predict ensemble of the 20 best packings (helix rotations and tilts) based on the neutral total energy ( E ) from a vast number (10 trillion) of potential packings for each of the four subtypes of the adenosine G protein‐coupled receptors (GPCRs), which are involved in many cytoprotective functions. We then used the DarwinDock Monte Carlo methods to predict the binding pose for the human A 3 adenosine receptor (hAA 3 R) for subtype selective agonists and antagonists. We found that all four A 3 agonists stabilize the 15th lowest conformation of apo‐hAA 3 R while also binding strongly to the 1st and 3rd. In contrast the four A 3 antagonists stabilize the 2nd or 3rd lowest conformation. These results show that different ligands can stabilize different GPCR conformations, which will likely affect function, complicating the design of functionally unique ligands. Interestingly all agonists lead to a trans χ1 angle for W6.48 that experiments on other GPCRs associate with G‐protein activation while all 20 apo‐AA 3 R conformations have a W6.48 gauche + χ1 angle associated experimentally with inactive GPCRs for other systems. Thus docking calculations have identified critical ligand‐GPCR structures involved with activation. We found that the predicted binding site for selective agonist Cl‐IB‐MECA to the predicted structure of hAA 3 R shows favorable interactions to three subtype variable residues, I253 6.58 , V169 EL2 , and Q167 EL2 , while the predicted structure for hAA 2A R shows weakened to the corresponding amino acids: T256 6.58 , E169 EL2 , and L167 EL2 , explaining the observed subtype selectivity. Proteins 2011; © 2011 Wiley‐Liss, Inc.