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Título: | Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation | Autor: | Luís, João P. Mata, Ana I. Simões, Carlos J. V. Brito, Rui M. M. |
Palavras-chave: | interleukin-1; interleukin-1 receptor type 1; flexible linker; molecular dynamics | Data: | 26-Fev-2022 | Projeto: | FCT - Ph.D. grant PD/BD/135292/2017 FCT - Ph.D. grant PD/BD/135289/2017 FCT - CPCA/A0/7316/2020 info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/QUI/00313/2019/PT |
Título da revista, periódico, livro ou evento: | International Journal of Molecular Sciences | Volume: | 23 | Número: | 5 | Resumo: | Interleukin-1 receptor type 1 (IL-1R1) is a key player in inflammation and immune responses. This receptor regulates IL-1 activity in two forms: as a membrane-bound form and as a soluble ectodomain. The details and differences between the conformational dynamics of the membrane-bound and the soluble IL-1R1 ectodomains (ECDs) remain largely elusive. Here, we study and compare the structural dynamics of the soluble and membrane-bound IL-1R1-ECDs using molecular dynamics (MD) simulations, focusing on the flexible interdomain linker of the ECD, as well as the spatial rearrangements between the Ig-like domains of the ECD. To explore the membrane-bound conformations, a full-length IL-1R1 structural model was developed and subjected to classical equilibrium MD. Comparative analysis of multiple MD trajectories of the soluble and the membrane-bound IL-1R1-ECDs reveals that (i) as somewhat expected, the extent of the visited "open-to-closed" transitional states differs significantly between the soluble and membrane-bound forms; (ii) the soluble form presents open-closed transitions, sampling a wider rotational motion between the Ig-like domains of the ECD, visiting closed and "twisted" conformations in higher extent, whereas the membrane-bound form is characterized by more conformationally restricted states; (iii) interestingly, the backbone dihedral angles of residues Glu202, Glu203 and Asn204, located in the flexible linker, display the highest variations during the transition between discrete conformational states detected in IL-1R1, thus appearing to work as the "central wheel of a clock's movement". The simulations and analyses presented in this contribution offer a deeper insight into the structure and dynamics of IL-1R1, which may be explored in a drug discovery setting. | URI: | https://hdl.handle.net/10316/103325 | ISSN: | 1422-0067 | DOI: | 10.3390/ijms23052599 | Direitos: | openAccess |
Aparece nas coleções: | I&D CQC - Artigos em Revistas Internacionais |
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