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|Title:||Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation||Authors:||Luís, João P.
Mata, Ana I.
Simões, Carlos J. V.
Brito, Rui M. M.
|Keywords:||interleukin-1; interleukin-1 receptor type 1; flexible linker; molecular dynamics||Issue Date:||26-Feb-2022||Project:||FCT - Ph.D. grant PD/BD/135292/2017
FCT - Ph.D. grant PD/BD/135289/2017
FCT - UID/QUI/00313/2019
FCT - CPCA/A0/7316/2020
|Serial title, monograph or event:||International Journal of Molecular Sciences||Volume:||23||Issue:||5||Abstract:||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:||http://hdl.handle.net/10316/103325||ISSN:||1422-0067||DOI:||10.3390/ijms23052599||Rights:||openAccess|
|Appears in Collections:||I&D CQC - Artigos em Revistas Internacionais|
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