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Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor |
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| Authors: | Dr Kai Fredriksson Dr Philip Lottmann Dr Sonja Hinz Iounut Onila Dr Aliaksei Shymanets Prof Christian Harteneck Prof Christa E Müller Prof Christian Griesinger Dr Thomas E Exner |
| Institution: | 1. Institute of Pharmacy, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany;2. Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany;3. Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, An der Immenburg 4, 53121 Bonn, Germany;4. Institute of Pharmacy, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Department of Chemistry and Zukunftskolleg, Universität Konstanz, 78457 Konstanz, Germany;5. Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Interfaculty Center of Pharmacogenomics and Pharmaceutical Research (ICePhA), University of Tübingen, Tübingen, Germany |
| Abstract: | G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2AR with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A2AR. |
| Keywords: | G-Protein-gekoppelte Rezeptoren Membranproteine NMR-Spektroskopie Proteinstrukturen Wirkstoffentwicklung |