5UIG

Crystal structure of adenosine A2A receptor bound to a novel triazole-carboximidamide antagonist

Summary for 5UIG

• Entry DOI: 10.2210/pdb5uig/pdb
• Descriptor: Adenosine receptor A2a,Soluble cytochrome b562,Adenosine receptor A2a, {[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: adenosine, a2a receptor, gpcr, vapor diffusion, allosteric, parkinson's disease, adenosine binding 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: 50364.75

Authors

Sun, B.,Bachhawat, P.,Ling-Hon Chu, M.,Ceska, T.,Sands, Z.,Lebon, F.,Kobilka, T.S.,Kobilka, B. (deposition date: 2017-01-13, release date: 2017-02-08, Last modification date: 2024-11-06)

Primary citation

Sun, B.,Bachhawat, P.,Chu, M.L.,Wood, M.,Ceska, T.,Sands, Z.A.,Mercier, J.,Lebon, F.,Kobilka, T.S.,Kobilka, B.K.
Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket.
Proc. Natl. Acad. Sci. U.S.A., 114:2066-2071, 2017

PubMed Abstract: The adenosine A receptor (AR) has long been implicated in cardiovascular disorders. As more selective AR ligands are being identified, its roles in other disorders, such as Parkinson's disease, are starting to emerge, and AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A receptor bound to compound 1 (Cmpd-1), a novel AR/-methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A receptor with a cytochrome b562-RIL (BRIL) fusion (AR-BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas AR-BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1-bound AR-BRIL prevented formation of the lattice observed with the ZM241385-bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr9 and Tyr271, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other AR structures, highlighting flexibility in the binding pocket that may facilitate the development of AR-selective compounds for the treatment of Parkinson's disease.

PubMed: 28167788
DOI: 10.1073/pnas.1621423114

Experimental method

X-RAY DIFFRACTION (3.5 Å)