Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870
Multiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report t...
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2019-11-01
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| Online Access: | https://elifesciences.org/articles/48822 |
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doaj-f2dd1514f1fb4cdfbfc8e25d3ba32b2f2021-05-05T18:07:08ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.48822Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870Ye Zhou0https://orcid.org/0000-0002-0489-3614Can Cao1Lingli He2Xianping Wang3Xuejun Cai Zhang4https://orcid.org/0000-0001-6726-3698National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, ChinaMultiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report the 3.5-angstrom crystal structure of mouse dopamine receptor D4 (DRD4) complexed with a subtype-selective antagonist, L745870. Our structure reveals a secondary binding pocket extended from the orthosteric ligand-binding pocket to a DRD4-specific crevice located between transmembrane helices 2 and 3. Additional mutagenesis studies suggest that the antagonist L745870 prevents DRD4 activation by blocking the relative movement between transmembrane helices 2 and 3. These results expand our knowledge of the molecular basis for the physiological functions of DRD4 and assist new drug design.https://elifesciences.org/articles/48822GPCRligand bindingantagonistDRD4dimerization |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Ye Zhou Can Cao Lingli He Xianping Wang Xuejun Cai Zhang |
| spellingShingle |
Ye Zhou Can Cao Lingli He Xianping Wang Xuejun Cai Zhang Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 eLife GPCR ligand binding antagonist DRD4 dimerization |
| author_facet |
Ye Zhou Can Cao Lingli He Xianping Wang Xuejun Cai Zhang |
| author_sort |
Ye Zhou |
| title |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 |
| title_short |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 |
| title_full |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 |
| title_fullStr |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 |
| title_full_unstemmed |
Crystal structure of dopamine receptor D4 bound to the subtype selective ligand, L745870 |
| title_sort |
crystal structure of dopamine receptor d4 bound to the subtype selective ligand, l745870 |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2019-11-01 |
| description |
Multiple subtypes of dopamine receptors within the GPCR superfamily regulate neurological processes through various downstream signaling pathways. A crucial question about the dopamine receptor family is what structural features determine the subtype-selectivity of potential drugs. Here, we report the 3.5-angstrom crystal structure of mouse dopamine receptor D4 (DRD4) complexed with a subtype-selective antagonist, L745870. Our structure reveals a secondary binding pocket extended from the orthosteric ligand-binding pocket to a DRD4-specific crevice located between transmembrane helices 2 and 3. Additional mutagenesis studies suggest that the antagonist L745870 prevents DRD4 activation by blocking the relative movement between transmembrane helices 2 and 3. These results expand our knowledge of the molecular basis for the physiological functions of DRD4 and assist new drug design. |
| topic |
GPCR ligand binding antagonist DRD4 dimerization |
| url |
https://elifesciences.org/articles/48822 |
| work_keys_str_mv |
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