7PYR

Crystal structure of the adenosine A2A receptor (A2A-PSB1-bRIL) in complex with preladenant conjugate PSB-2115

Summary for 7PYR

• Entry DOI: 10.2210/pdb7pyr/pdb
• Descriptor: Adenosine receptor A2a,Soluble cytochrome b562,Adenosine receptor A2a, CHOLESTEROL, 2-[2-[2-[2-[2-[2-[4-[4-[2-[7-azanyl-4-(furan-2-yl)-3,5,6,8,10,11-hexazatricyclo[7.3.0.0^{2,6}]dodeca-1(9),2,4,7,11-pentaen-10-yl]ethyl]piperazin-1-yl]phenoxy]ethanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-~{N}-[5-[2,2-bis(fluoranyl)-4,6,10,12-tetramethyl-1,3-diaza-2$l^{4}-boratricyclo[7.3.0.0^{3,7}]dodeca-4,6,9,11-tetraen-8-yl]pentyl]ethanamide, ... (7 entities in total)
• Functional Keywords: gpcr, membrane protein, a2a, g protein-coupled receptor, adenosine receptor, preladenant
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 60928.25

Authors

Claff, T.,Klapschinski, T.A.,Tiruttani Subhramanyam, U.K.,Vaassen, V.J.,Schlegel, J.G.,Vielmuth, C.,Voss, J.H.,Labahn, J.,Muller, C.E. (deposition date: 2021-10-11, release date: 2022-03-02, Last modification date: 2024-10-16)

Primary citation

Claff, T.,Klapschinski, T.A.,Tiruttani Subhramanyam, U.K.,Vaassen, V.J.,Schlegel, J.G.,Vielmuth, C.,Voss, J.H.,Labahn, J.,Muller, C.E.
Single Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A 2A Receptor with Preladenant Conjugates.
Angew.Chem.Int.Ed.Engl., 61:e202115545-e202115545, 2022

PubMed Abstract: The G protein-coupled adenosine A receptor (A AR) is an important new (potential) drug target in immuno-oncology, and for neurodegenerative diseases. Preladenant and its derivatives belong to the most potent A AR antagonists displaying exceptional selectivity. While crystal structures of the human A AR have been solved, mostly using the A -StaR2 protein that bears 9 point mutations, co-crystallization with Preladenant derivatives has so far been elusive. We developed a new A AR construct harboring a single point mutation (S91 K) which renders it extremely thermostable. This allowed the co-crystallization of two novel Preladenant derivatives, the polyethylene glycol-conjugated (PEGylated) PSB-2113, and the fluorophore-labeled PSB-2115. The obtained crystal structures (2.25 Å and 2.6 Å resolution) provide explanations for the high potency and selectivity of Preladenant derivatives. They represent the first crystal structures of a GPCR in complex with PEG- and fluorophore-conjugated ligands. The applied strategy is predicted to be applicable to further class A GPCRs.

PubMed: 35174942
DOI: 10.1002/anie.202115545

Experimental method

X-RAY DIFFRACTION (2.6 Å)