Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs
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 flexibilit...
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Published in | Scientific reports Vol. 8; no. 1; pp. 897 - 10 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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London
Nature Publishing Group UK
17.01.2018
Nature Publishing Group |
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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, F
6.52
. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery. |
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AbstractList | 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, F
6.52
. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery. 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, F . Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery. 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. 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. N.F. acknowledges support from Generalitat de Catalunya (FI-Agaur). GDF acknowledges support from MINECO (BIO2014-53095-P) and FEDER. We also thank all the volunteers of GPUGRID who donated GPU computing time to the project. |
ArticleNumber | 897 |
Author | Ferruz, Noelia Sciabola, Simone Zou, Yaozhong Vanase-Frawley, Michelle A. Nelson, Robin T. Doerr, Stefan Kormos, Bethany L. Villalobos, Anabella Chen, Xiaomin Marr, Eric S. Wager, Travis T. De Fabritiis, Gianni Hou, Xinjun |
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Snippet | 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)... |
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SubjectTerms | 119/118 631/154/309/606 631/92/606 Animals BASIC BIOLOGICAL SCIENCES Binding Sites - physiology Cell Line Computational chemistry Crystal structure Crystallography, X-Ray - methods Dopamine Dopamine D3 receptor Dopamine D3 receptors Drug development G protein-coupled receptors Humanities and Social Sciences Humans Ligands Macromolecules Markov state models Molecular Docking Simulation - methods Molecular dynamics Molecular Dynamics Simulation multidisciplinary Mutagenesis, Site-Directed - methods Protein Binding - physiology Protein structure Receptors, Dopamine D3 - antagonists & inhibitors Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - metabolism Salicylamides - chemistry Salicylamides - metabolism Science Science (multidisciplinary) Sf9 Cells Site-directed mutagenesis |
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Title | Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs |
URI | https://link.springer.com/article/10.1038/s41598-018-19345-7 https://www.ncbi.nlm.nih.gov/pubmed/29343833 https://www.proquest.com/docview/1988510451 https://recercat.cat/handle/2072/315054 https://www.osti.gov/servlets/purl/1440593 https://pubmed.ncbi.nlm.nih.gov/PMC5772633 |
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