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Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

eLife, 2020-01, Vol.9 [Peer Reviewed Journal]

COPYRIGHT 2020 eLife Science Publications, Ltd. ;2020. This work is published under http://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 2050-084X ;EISSN: 2050-084X ;DOI: 10.7554/elife.52189 ;PMID: 31985399

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Title:
Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism
Author: Lane, J Robert ; Abramyan, Ara M ; Adhikari, Pramisha ; Keen, Alastair C ; Lee, Kuo-Hao ; Sanchez, Julie ; Verma, Ravi Kumar ; Lim, Herman D ; Yano, Hideaki ; Javitch, Jonathan A ; Shi, Lei
Subjects: Analysis ; Aripiprazole ; Binding Sites ; Biochemistry and Chemical Biology ; Conformation ; Crystal structure ; Dopamine ; Dopamine Agonists - chemistry ; Dopamine Agonists - metabolism ; Dopamine Antagonists - chemistry ; Dopamine Antagonists - metabolism ; dopamine d2 receptor ; Dopamine D2 receptors ; Dopamine D3 receptors ; Dopamine receptors ; Drug Discovery ; Hypotheses ; inverse agonism ; Ligands ; molecular dynamics ; Molecular Dynamics Simulation ; Mutation ; na+ sensitivity ; Phenols (Class of compounds) ; Prescriptions (Drugs) ; Protein Binding ; Protein Conformation ; Proteins ; Receptors, Dopamine D2 - chemistry ; Receptors, Dopamine D2 - metabolism ; Receptors, Dopamine D3 - chemistry ; Receptors, Dopamine D3 - metabolism ; Risperidone ; Risperidone - chemistry ; Risperidone - metabolism ; Salicylamides - chemistry ; Salicylamides - metabolism ; Simulation ; Structural Biology and Molecular Biophysics
Is Part Of: eLife, 2020-01, Vol.9
Description: By analyzing and simulating inactive conformations of the highly homologous dopamine D and D receptors (D R and D R), we find that eticlopride binds D R in a pose very similar to that in the D R/eticlopride structure but incompatible with the D R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na -sensitive eticlopride and Na -insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D R/risperidone structure to an extended conformation similar to that in the D R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.
Publisher: England: eLife Science Publications, Ltd
Language: English
Identifier: ISSN: 2050-084X
EISSN: 2050-084X
DOI: 10.7554/elife.52189
PMID: 31985399
Source: MEDLINE
PubMed Central
ROAD: Directory of Open Access Scholarly Resources
ProQuest Central
DOAJ Directory of Open Access Journals

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Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

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