8GNG

Crystal structure of human adenosine A2A receptor in complex with istradefylline.

Summary for 8GNG

• Entry DOI: 10.2210/pdb8gng/pdb
• Related: 8GNE
• Descriptor: Adenosine receptor A2a, antibody fab fragment light chain, antibody fab fragment heavy chain, ... (8 entities in total)
• Functional Keywords: adenosine a2a receptor, istradefylline, neutral antagonist, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 174796.92

Authors

Suzuki, M.,Saito, J.,Miyagi, H.,Yasunaga, M. (deposition date: 2022-08-23, release date: 2023-03-22, Last modification date: 2024-11-13)

Primary citation

Ohno, Y.,Suzuki, M.,Asada, H.,Kanda, T.,Saki, M.,Miyagi, H.,Yasunaga, M.,Suno, C.,Iwata, S.,Saito, J.I.,Uchida, S.
In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A 2A Receptor Antagonist/Inverse Agonist.
Mol.Pharmacol., 103:311-324, 2023

PubMed Abstract: KW-6356 is a novel adenosine A (A) receptor antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing "OFF" episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined cocrystal structures of A receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A receptor (the -log of inhibition constant = 9.93 ± 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 ± 0.006 minute for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, whereas istradefylline exhibits surmountable antagonism. Crystallography of KW-6356- and istradefylline-bound A receptor have indicated that interactions with His250 and Trp246 are essential for the inverse agonism, whereas the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important differences in vivo and help predict better clinical performance. SIGNIFICANCE STATEMENT: KW-6356 is a potent and selective adenosine A receptor antagonist/inverse agonist and exhibits insurmountable antagonism, whereas istradefylline, a first-generation adenosine A receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline.

PubMed: 36894319
DOI: 10.1124/molpharm.122.000633

Experimental method

X-RAY DIFFRACTION (3.2 Å)