Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 1000+ Conferences, 1000+ Symposiums and 1000+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business.

Explore and learn more about Conference Series Ltd: World’s leading Event Organizer

Back

Biography

E. Demet Akten is working on the protein dynamics of b2-adrenergic receptor, in order to understand the allosteric coupling behavior that exists between the intra- and extracellular parts of the receptor. She is also developing screening techniques for the same protein to better discriminate agonists from antagonists or inverse agonists. 

Abstract

Background: This study investigates the allosteric coupling that exists between the intra- and extracellular parts
of human β2-AR, in the presence of intracellular loop 3 (ICL3), which is missing in all crystallographic experiments and most of the simulation studies. Our 1 μs long MD run has revealed a transition to an alternative inactive state of the receptor, in which ICL3 packed under 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. Independent runs with a total duration of 4 μs were carried out to further investigate this inactive state with packed ICL3 and the allosteric coupling event. Results: In all three independent unrestrained runs, ICL3 preserved its initially packed conformation during 500 ns long simulation, 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 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 ICL3 from its locked state. Conclusions: 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 receptor’s core.