Internal water channel formation in CXCR4 is crucial for Gi-protein coupling upon activation by CXCL12
| Autor: | Ya-Tzu Li, Shinn Jong Jiang, Sheng-Feng Pan, Yu-Chen Yeh, Kingsley Theras Primus Dass, Chun-Chun Chang, Hao-Jen Hsu, Je-Wen Liou |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Chemokine education Biochemistry lcsh:Chemistry 03 medical and health sciences Chemokine receptor 0302 clinical medicine Materials Chemistry Environmental Chemistry Tyrosine biology Chemistry Cell migration Translation (biology) General Chemistry biological factors Transmembrane protein Coupling (electronics) 030104 developmental biology lcsh:QD1-999 Cytoplasm 030220 oncology & carcinogenesis embryonic structures biology.protein Biophysics biological phenomena cell phenomena and immunity |
| Zdroj: | Communications Chemistry, Vol 3, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2399-3669 |
| DOI: | 10.1038/s42004-020-00383-0 |
| Popis: | Chemokine receptor CXCR4 is a major drug target for numerous diseases because of its involvement in the regulation of cell migration and the developmental process. In this study, atomic-level molecular dynamics simulations were used to determine the activation mechanism and internal water formation of CXCR4 in complex with chemokine CXCL12 and Gi-protein. The results indicated that CXCL12-bound CXCR4 underwent transmembrane 6 (TM6) outward movement and a decrease in tyrosine toggle switch by eliciting the breakage of hydrophobic layer to form a continuous internal water channel. In the GDP-bound Gαi-protein state, the rotation and translation of the α5-helix of Gαi-protein toward the cytoplasmic pocket of CXCR4 induced an increase in interdomain distance for GDP leaving. Finally, an internal water channel formation model was proposed based on our simulations for CXCL12-bound CXCR4 in complex with Gαi-protein upon activation for downstream signaling. This model could be useful in anticancer drug development. Understanding the downstream signal transduction process of the CXCL12–CXCR4–Gαi tricomplex could prove useful in the development of anticancer and antimetastatic drugs. Here the authors propose an internal water channel formation model for CXCL12-bound CXCR4 in complex with Gαi-protein upon activation for downstream signaling. |
| Databáze: | OpenAIRE |
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