Structure of the Adenosine A(1) Receptor Reveals the Basis for Subtype Selectivity
Alisa Glukhova, David M Thal, Anh T Nguyen, Elizabeth A Vecchio, Manuela Jorg, Peter J Scammells, Lauren T May, Patrick M Sexton, Arthur Christopoulos
Cell | CELL PRESS | Published : 2017
The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
Data collection was undertaken at the MX2 beamline at the Australian synchrotron. This work was funded by the National Health and Medical Research Council of Australia (NHMRC) Program Grant APP1055134 and Project Grant APP1084246. A.T.N. is a recipient of an Australian Endeavour Scholarship and Fellowship. L.T.M. is a recipient of an Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA), A.C. is a Senior Principal Research Fellow, and P.M.S. is a Principal Research Fellow, of the NHMRC. E.A.V. holds an Australian Postgraduate Award and an Australian Cancer Therapeutics scholarship. We thank Prof. Brian Kobilka for helpful discussions.