Single Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A 2A Receptor with Preladenant Conjugates.

Autor: Claff T; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Klapschinski TA; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Tiruttani Subhramanyam UK; Centre for Structural Systems Biology (CSSB), Notkestraße 85, 22607, Hamburg, Germany.; Research Centre Jülich, Institute of Complex Systems (IBI-7), Wilhelm-Johnen-Straße, 52425, Jülich, Germany., Vaaßen VJ; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Schlegel JG; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Vielmuth C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Voß JH; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany., Labahn J; Centre for Structural Systems Biology (CSSB), Notkestraße 85, 22607, Hamburg, Germany.; Research Centre Jülich, Institute of Complex Systems (IBI-7), Wilhelm-Johnen-Straße, 52425, Jülich, Germany., Müller CE; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2022 May 23; Vol. 61 (22), pp. e202115545. Date of Electronic Publication: 2022 Mar 24.
DOI: 10.1002/anie.202115545
Abstrakt: The G protein-coupled adenosine A 2A receptor (A 2A 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 2A AR antagonists displaying exceptional selectivity. While crystal structures of the human A 2A AR have been solved, mostly using the A 2A -StaR2 protein that bears 9 point mutations, co-crystallization with Preladenant derivatives has so far been elusive. We developed a new A 2A AR construct harboring a single point mutation (S91 3.39 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.
(© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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