Crystal structure of the adenosine A 2A receptor bound to an antagonist reveals a potential allosteric pocket
| Autor: | Zara A. Sands, Florence Lebon, Matthew Ling-Hon Chu, Tong Sun Kobilka, Joël Mercier, Priti Bachhawat, Tom Ceska, Brian K. Kobilka, Martyn Wood, Bingfa Sun |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Multidisciplinary Chemistry Ligand Stereochemistry Allosteric regulation Antagonist Adenosine A2A receptor Crystal structure Adenosine 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine Tyrosine Receptor 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:2066-2071 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1621423114 |
| Popis: | The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 A resolution. The A2A receptor with a cytochrome b562-RIL (BRIL) fusion (A2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A2AR–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 A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35 and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson’s disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|