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Investigation of allosteric coupling in human β2-adrenergic receptor in the presence of intracellular loop 3

Overview of attention for article published in BMC Structural Biology, July 2016
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Title
Investigation of allosteric coupling in human β2-adrenergic receptor in the presence of intracellular loop 3
Published in
BMC Structural Biology, July 2016
DOI 10.1186/s12900-016-0061-9
Pubmed ID
Authors

Canan Ozgur, Pemra Doruker, E. Demet Akten

Abstract

This study investigates the allosteric coupling that exists between the intra- and extracellular parts of human β2-adrenergic receptor (β2-AR), in the presence of the intracellular loop 3 (ICL3), which is missing in all crystallographic experiments and most of the simulation studies reported so far. Our recent 1 μs long MD run has revealed a transition to the so-called very inactive state of the receptor, in which ICL3 packed under the G protein's binding cavity and completely blocked its accessibility to G protein. Simultaneously, an outward tilt of transmembrane helix 5 (TM5) caused an expansion of the extracellular ligand-binding site. In the current study, we performed independent runs with a total duration of 4 μs to further investigate the very inactive state with packed ICL3 and the allosteric coupling event (three unrestrained runs and five runs with bond restraints at the ligand-binding site). In all three independent unrestrained runs (each 500 ns long), ICL3 preserved its initially packed/closed conformation within the studied time frame, suggesting an inhibition of the receptor's activity. Specific bond restraints were later imposed between some key residues at the ligand-binding site, which have been experimentally determined to interact with the ligand. Restraining the binding site region to an open state facilitated ICL3 closure, whereas a relatively constrained/closed binding site hindered ICL3 packing. However, the reverse operation, i.e. opening of the packed ICL3, could not be realized by restraining the binding site region to a closed state. Thus, any attempt failed to free the ICL3 from its locked state due to the presence of persistent hydrogen bonds. Overall, our simulations indicated that starting with very inactive states, the receptor stayed almost irreversibly inhibited, which in turn decreased the overall mobility of the receptor. Bond restraints which represented the geometric restrictions caused by ligands of various sizes when bound at the ligand-binding site, induced the expected conformational changes in TM5, TM6 and consequently, ICL3. Still, once ICL3 was packed, the allosteric coupling became ineffective due to strong hydrogen bonds connecting ICL3 to the core of the receptor.

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Mendeley readers

The data shown below were compiled from readership statistics for 33 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 33 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 7 21%
Student > Ph. D. Student 6 18%
Researcher 5 15%
Student > Bachelor 4 12%
Student > Doctoral Student 2 6%
Other 5 15%
Unknown 4 12%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 12 36%
Agricultural and Biological Sciences 6 18%
Computer Science 2 6%
Neuroscience 2 6%
Engineering 2 6%
Other 4 12%
Unknown 5 15%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 July 2016.
All research outputs
#4,240,556
of 8,037,685 outputs
Outputs from BMC Structural Biology
#65
of 143 outputs
Outputs of similar age
#141,030
of 258,923 outputs
Outputs of similar age from BMC Structural Biology
#2
of 4 outputs
Altmetric has tracked 8,037,685 research outputs across all sources so far. This one is in the 27th percentile – i.e., 27% of other outputs scored the same or lower than it.
So far Altmetric has tracked 143 research outputs from this source. They receive a mean Attention Score of 2.7. This one is in the 37th percentile – i.e., 37% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 258,923 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 35th percentile – i.e., 35% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 4 others from the same source and published within six weeks on either side of this one. This one has scored higher than 2 of them.