Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor

被引：14

作者：

Fredriksson, Kai ^{[1
,2
,6
]}

Lottmann, Philip ^{[3
]}

Hinz, Sonja ^{[4
]}

Onila, Iounut ^{[1
,2
]}

Shymanets, Aliaksei ^{[5
]}

Harteneck, Christian ^{[5
]}

Mueller, Christa E. ^{[4
]}

Griesinger, Christian ^{[3
]}

Exner, Thomas E. ^{[1
,2
]}

机构：

[1] Eberhard Karls Univ Tubingen, Inst Pharm, Morgenstelle 8, D-72076 Tubingen, Germany

[2] Univ Konstanz, Dept Chem & Zukunftskolleg, D-78457 Constance, Germany

[3] Max Planck Inst Biophys Chem, Fassberg 11, D-37077 Gottingen, Germany

[4] Univ Bonn, Pharma Zentrum Bonn, Pharmazeut Chem, Inst Pharmazeut, Immenburg 4, D-53121 Bonn, Germany

[5] Univ Tubingen, Interfac Ctr Pharmacogenom & Pharmaceut Res ICePh, Inst Expt & Clin Pharmacol & Toxicol, Dept Pharmacol & Expt Therapy, Tubingen, Germany

[6] Tech Univ Munich, Fak Chem, Lichtenbergstr 4, D-85748 Garching, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2017年 / 56卷 / 21期

关键词：

drug design; G-protein-coupled receptors; membrane proteins; NMR; protein structures; TRANSFER DIFFERENCE NMR; DRUG DESIGN; PROTEIN; DOCKING;

D O I：

10.1002/anie.201612547

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 A(2A) 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 A(2A)R 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 A(2A)R.

引用

页码：5750 / 5754

页数：5

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