5UEN

Crystal structure of the human adenosine A1 receptor A1AR-bRIL in complex with the covalent antagonist DU172 at 3.2A resolution

Summary for 5UEN

• Entry DOI: 10.2210/pdb5uen/pdb
• Descriptor: Adenosine receptor A1,Soluble cytochrome b562,Adenosine receptor A1, 4-{[3-(8-cyclohexyl-2,6-dioxo-1-propyl-1,2,6,7-tetrahydro-3H-purin-3-yl)propyl]carbamoyl}benzene-1-sulfonyl fluoride, OLEIC ACID (3 entities in total)
• Functional Keywords: gpcr, transmembrane, receptor, adenosine, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 96136.47

Authors

Glukhova, A.,Thal, D.M.,Nguyen, A.T.,Vecchio, E.A.,Jorg, M.,Scammells, P.J.,May, L.T.,Sexton, P.M.,Christopoulos, A. (deposition date: 2017-01-03, release date: 2017-03-01, Last modification date: 2023-10-04)

Primary citation

Glukhova, A.,Thal, D.M.,Nguyen, A.T.,Vecchio, E.A.,Jorg, M.,Scammells, P.J.,May, L.T.,Sexton, P.M.,Christopoulos, A.
Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity.
Cell, 168:867-877.e13, 2017

PubMed Abstract: The adenosine A receptor (A-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 A-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A receptor (A-AR) structure. Mutational and computational analysis of A-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-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.

PubMed: 28235198
DOI: 10.1016/j.cell.2017.01.042

Experimental method

X-RAY DIFFRACTION (3.2 Å)