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Conformational Complexity and Dynamics in a GPCR Revealed by NMR Spectroscopy

59 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Jun Xu

Jun Xu

Tsinghua University, School of Medicine, Beijing Advanced Innovation Center for Structural Biology

Yunfei Hu

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Jonas Kaindl

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Philipp Risel

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Harald Hübner

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Shoji Meada

Stanford University, School of Medicine, Department of Molecular and Cellular Physiology

Xiaogang Niu

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Hongwei Li

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Peter Gmeiner

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Changwen Jin

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Brian K. Koblika

Tsinghua University, School of Medicine, Beijing Advanced Innovation Center for Structural Biology; Stanford University, School of Medicine, Department of Molecular and Cellular Physiology

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Abstract

The M2 muscarinic acetylcholine receptor (M2R) is a prototypical GPCR that plays important roles in regulating heart rate and central nerves system functions. Crystal structures provide snapshots of the M2R in inactive and active states; yet the allosteric link between the ligand binding pocket and cytoplasmic surface remains poorly understood. Here we employed solution NMR to examine the structure and dynamics of the M2R labeled with 13CH3-ɛ-methionine upon binding to various orthosteric and allosteric ligands having a range of efficacy for both G protein activation and arrestin recruitment. We observed ligand-specific changes in the NMR spectra of 13CH3-ɛ-methionine probes in the M2R extracellular domain, transmembrane core and cytoplasmic surface, allowing us to correlate ligand structure with changes in receptor structure and dynamics. We show that the M2R has a complex energy landscape where ligands with different efficacy profiles stabilize distinct receptor conformations.

Suggested Citation

Xu, Jun and Hu, Yunfei and Kaindl, Jonas and Risel, Philipp and Hübner, Harald and Meada, Shoji and Niu, Xiaogang and Li, Hongwei and Gmeiner, Peter and Jin, Changwen and Koblika, Brian K., Conformational Complexity and Dynamics in a GPCR Revealed by NMR Spectroscopy. Available at SSRN: https://ssrn.com/abstract=3305551 or http://dx.doi.org/10.2139/ssrn.3305551
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jun Xu

Tsinghua University, School of Medicine, Beijing Advanced Innovation Center for Structural Biology

Beijing, 100084
China

Yunfei Hu

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Beijing, 100084
China

Jonas Kaindl

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Nikolaus-Fiebiger-Straße 10
91058 Erlangen
Germany

Philipp Risel

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Nikolaus-Fiebiger-Straße 10
91058 Erlangen
Germany

Harald Hübner

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Nikolaus-Fiebiger-Straße 10
91058 Erlangen
Germany

Shoji Meada

Stanford University, School of Medicine, Department of Molecular and Cellular Physiology

Stanford, CA 94305
United States

Xiaogang Niu

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Beijing, 100084
China

Hongwei Li

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center

Beijing, 100084
China

Peter Gmeiner

Friedrich-Alexander-Universität Erlangen-Nürnberg, Medicinal Chemistry, Department of Chemistry and Pharmacy

Nikolaus-Fiebiger-Straße 10
91058 Erlangen
Germany

Changwen Jin

Peking University, School of Life Sciences, College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center ( email )

Beijing, 100084
China

Brian K. Koblika (Contact Author)

Tsinghua University, School of Medicine, Beijing Advanced Innovation Center for Structural Biology ( email )

Beijing, 100084
China

Stanford University, School of Medicine, Department of Molecular and Cellular Physiology ( email )

Stanford, CA 94305
United States

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