Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket

Sun, Bingfa; Bachhawat, Priti; Chu, Matthew Ling-Hon; Wood, Martyn; Ceska, Tom; Sands, Zara A.; Mercier, Joel; Lebon, Florence; Kobilka, Tong Sun; Kobilka, Brian K.

doi:10.1073/pnas.1621423114

Title: Crystal structure of the adenosine A_2A receptor bound to an antagonist reveals a potential allosteric pocket

Journal Article · Mon Feb 06 00:00:00 EST 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1621423114· OSTI ID:1347032

Sun, Bingfa ^[1]; Bachhawat, Priti ^[1]; Chu, Matthew Ling-Hon ^[1]; Wood, Martyn ^[2]; Ceska, Tom ^[3]; Sands, Zara A. ^[2]; Mercier, Joel ^[2]; Lebon, Florence ^[2]; Kobilka, Tong Sun ^[1]; Kobilka, Brian K. ^[4]

ConfometRx, Inc., Santa Clara, CA (United States)
UCB Pharma, Braine-l’Alleud (Belgium)
UCB Pharma, Slough (United Kingdom)
ConfometRx, Inc., Santa Clara, CA (United States); Stanford Univ. School of Medicine, CA (United States)

The adenosine A_2Areceptor (A_2AR) has long been implicated in cardiovascular disorders. As more selective A_2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A_2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A_2Areceptor bound to compound 1 (Cmpd-1), a novel A_2AR/N-methyld-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A_2Areceptor with a cytochrome b562-RIL (BRIL) fusion (A_2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A_2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A_2AR–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 A_2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr9^1.35and Tyr271^7.36, which are critical for the formation of the exosite. As a result, the structure reveals insights into antagonist binding that are not observed in other A_2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A_2AR-selective compounds for the treatment of Parkinson’s disease.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1347032

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 8; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 88 works

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Title: Crystal structure of the adenosine A2A receptor bound to an antagonist reveals a potential allosteric pocket

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Title: Crystal structure of the adenosine A_2A receptor bound to an antagonist reveals a potential allosteric pocket