Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor
The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine...
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/7/3702 |
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| author | Xiaoyuan Ma Marta Arimont Segura Barbara Zarzycka Henry F. Vischer Rob Leurs |
| author_facet | Xiaoyuan Ma Marta Arimont Segura Barbara Zarzycka Henry F. Vischer Rob Leurs |
| author_sort | Xiaoyuan Ma |
| collection | DOAJ |
| description | The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R127<sup>3.52×52</sup>H, R139<sup>34.57×57</sup>H, R409<sup>6.29×29</sup>H, and E410<sup>6.30×30</sup>K, were selected for the histamine H<sub>1</sub> receptor (H<sub>1</sub>R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E410<sup>6.30×30</sup>K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H<sub>1</sub>R, whereas the opposite was observed for R127<sup>3.52×52</sup>H, R139<sup>34.57×57</sup>H, and R409<sup>6.29×29</sup>H. The E410<sup>6.30×30</sup>K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H<sub>1</sub>R, whereas antagonist affinity was not affected. These data support the hypothesis that the E410<sup>6.30×30</sup>K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H<sub>1</sub>R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:39:47Z |
| publishDate | 2021-04-01 |
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| spelling | doaj.art-97c17a37c12e461c853703e5720744722023-11-21T13:57:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01227370210.3390/ijms22073702Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> ReceptorXiaoyuan Ma0Marta Arimont Segura1Barbara Zarzycka2Henry F. Vischer3Rob Leurs4Division of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The NetherlandsDivision of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The NetherlandsDivision of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The NetherlandsDivision of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The NetherlandsDivision of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The NetherlandsThe Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R127<sup>3.52×52</sup>H, R139<sup>34.57×57</sup>H, R409<sup>6.29×29</sup>H, and E410<sup>6.30×30</sup>K, were selected for the histamine H<sub>1</sub> receptor (H<sub>1</sub>R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E410<sup>6.30×30</sup>K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H<sub>1</sub>R, whereas the opposite was observed for R127<sup>3.52×52</sup>H, R139<sup>34.57×57</sup>H, and R409<sup>6.29×29</sup>H. The E410<sup>6.30×30</sup>K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H<sub>1</sub>R, whereas antagonist affinity was not affected. These data support the hypothesis that the E410<sup>6.30×30</sup>K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H<sub>1</sub>R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process.https://www.mdpi.com/1422-0067/22/7/3702missense variationG protein-coupled receptorhistamine H<sub>1</sub> receptorionic lockconstitutive activity |
| spellingShingle | Xiaoyuan Ma Marta Arimont Segura Barbara Zarzycka Henry F. Vischer Rob Leurs Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor International Journal of Molecular Sciences missense variation G protein-coupled receptor histamine H<sub>1</sub> receptor ionic lock constitutive activity |
| title | Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor |
| title_full | Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor |
| title_fullStr | Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor |
| title_full_unstemmed | Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor |
| title_short | Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410<sup>6.30×30</sup>K Variant in the Histamine H<sub>1</sub> Receptor |
| title_sort | analysis of missense variants in the human histamine receptor family reveals increased constitutive activity of e410 sup 6 30 30 sup k variant in the histamine h sub 1 sub receptor |
| topic | missense variation G protein-coupled receptor histamine H<sub>1</sub> receptor ionic lock constitutive activity |
| url | https://www.mdpi.com/1422-0067/22/7/3702 |
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