This title appears in the Scientific Report :
2017
Please use the identifier:
http://dx.doi.org/10.1038/srep45761 in citations.
Please use the identifier: http://hdl.handle.net/2128/14205 in citations.
Structural heterogeneity of the $μ$-opioid receptor’s conformational ensemble in the apo state
Structural heterogeneity of the $μ$-opioid receptor’s conformational ensemble in the apo state
G-protein coupled receptors (GPCRs) are the largest and most pharmaceutically relevant family of membrane proteins. Here, fully unbiased, enhanced sampling simulations of a constitutively active mutant (CAM) of a class A GPCR, the μ-opioid receptor (μOR), demonstrates repeated transitions between th...
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Personal Name(s): | Sena, Diniz M. |
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Cong, Xiaojing (Corresponding author) / Giorgetti, Alejandro / Kless, Achim / Carloni, Paolo (Corresponding author) | |
Contributing Institute: |
Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5 |
Published in: | Scientific reports, 7 (2017) S. 45761 |
Imprint: |
London
Nature Publishing Group
2017
|
PubMed ID: |
28368046 |
DOI: |
10.1038/srep45761 |
Document Type: |
Journal Article |
Research Program: |
(Dys-)function and Plasticity |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/14205 in citations.
G-protein coupled receptors (GPCRs) are the largest and most pharmaceutically relevant family of membrane proteins. Here, fully unbiased, enhanced sampling simulations of a constitutively active mutant (CAM) of a class A GPCR, the μ-opioid receptor (μOR), demonstrates repeated transitions between the inactive (IS) and active-like (AS-L) states. The interconversion features typical activation/inactivation patterns involving established conformational rearrangements of conserved residues. By contrast, wild-type μOR remains in IS during the same course of simulation, consistent with the low basal activity of the protein. The simulations point to an important role of residue W2936.48 at the “toggle switch” in the mutation-induced constitutive activation. Such role has been already observed for other CAMs of class A GPCRs. We also find a significantly populated intermediate state, rather similar to IS. Based on the remarkable accord between simulations and experiments, we suggest here that this state, which has escaped so far experimental characterization, might constitute an early step in the activation process of the apo μOR CAM. |