Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs
Abstract
The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.
- Authors:
-
- Univ. Pompeu Fabra, Barcelona (Spain); Acellera, Barcelona (Spain)
- Pfizer Worldwide Research and Development, Groton, CT (United States)
- Pfizer Worldwide Research and Development, Cambridge, MA (United States)
- Univ. Pompeu Fabra, Barcelona (Spain); Acellera, Barcelona (Spain); Inst. Catalana de Recerca i Estudis Avançats (ICREA), Barcelona (Spain)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- Ministry of Economic Affairs and Digital Transformation of Spain (MINECO); FEDER
- OSTI Identifier:
- 1440593
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Computational chemistry
Citation Formats
Ferruz, Noelia, Doerr, Stefan, Vanase-Frawley, Michelle A., Zou, Yaozhong, Chen, Xiaomin, Marr, Eric S., Nelson, Robin T., Kormos, Bethany L., Wager, Travis T., Hou, Xinjun, Villalobos, Anabella, Sciabola, Simone, and De Fabritiis, Gianni. Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs. United States: N. p., 2018.
Web. doi:10.1038/s41598-018-19345-7.
Ferruz, Noelia, Doerr, Stefan, Vanase-Frawley, Michelle A., Zou, Yaozhong, Chen, Xiaomin, Marr, Eric S., Nelson, Robin T., Kormos, Bethany L., Wager, Travis T., Hou, Xinjun, Villalobos, Anabella, Sciabola, Simone, & De Fabritiis, Gianni. Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs. United States. https://doi.org/10.1038/s41598-018-19345-7
Ferruz, Noelia, Doerr, Stefan, Vanase-Frawley, Michelle A., Zou, Yaozhong, Chen, Xiaomin, Marr, Eric S., Nelson, Robin T., Kormos, Bethany L., Wager, Travis T., Hou, Xinjun, Villalobos, Anabella, Sciabola, Simone, and De Fabritiis, Gianni. Wed .
"Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs". United States. https://doi.org/10.1038/s41598-018-19345-7. https://www.osti.gov/servlets/purl/1440593.
@article{osti_1440593,
title = {Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs},
author = {Ferruz, Noelia and Doerr, Stefan and Vanase-Frawley, Michelle A. and Zou, Yaozhong and Chen, Xiaomin and Marr, Eric S. and Nelson, Robin T. and Kormos, Bethany L. and Wager, Travis T. and Hou, Xinjun and Villalobos, Anabella and Sciabola, Simone and De Fabritiis, Gianni},
abstractNote = {The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.},
doi = {10.1038/s41598-018-19345-7},
journal = {Scientific Reports},
number = 1,
volume = 8,
place = {United States},
year = {Wed Jan 17 00:00:00 EST 2018},
month = {Wed Jan 17 00:00:00 EST 2018}
}
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Complete protein–protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling
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Trends in GPCR drug discovery: new agents, targets and indications
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Activation-Induced Conformational Changes of Dopamine D3 Receptor Promote the Formation of the Internal Water Channel
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Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme
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Pathway and mechanism of drug binding to G-protein-coupled receptors
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Activation mechanism of the 2-adrenergic receptor
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Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices
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PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations
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What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?
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Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist
journal, November 2010
- Chien, E. Y. T.; Liu, W.; Zhao, Q.
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D 4 dopamine receptor high-resolution structures enable the discovery of selective agonists
journal, October 2017
- Wang, Sheng; Wacker, Daniel; Levit, Anat
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