Effect of intracellular loop 3 on intrinsic dynamics of human 2-adrenergic receptor

Loading...
Thumbnail Image

Date

2013

Authors

Ozcan, Ozer
Uyar, Arzu
Doruker, Pemra
Akten, Ebru Demet

Journal Title

Journal ISSN

Volume Title

Publisher

Bmc

Research Projects

Organizational Units

Journal Issue

Abstract

Background: To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human beta(2)-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 mu s molecular dynamics (MD) simulation at 310 K. Results: After around 600 ns, the loop model started a transition to a very inactive conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein's binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 angstrom from 11 angstrom, which was further elaborated by docking studies. Conclusions: The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the very inactive state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes.

Description

Keywords

Protein-Coupled Receptor, Beta(2) Adrenergic-Receptor, Human Beta-2-Adrenergic Receptor, Molecular-Dynamics, Crystal-Structure, Binding-Site, Cytoplasmic Domains, Partial Agonists, Model, Activation, Protein-Coupled Receptor, Beta(2) Adrenergic-Receptor, Human Beta-2-Adrenergic Receptor, Molecular-Dynamics, Crystal-Structure, ICL3, Binding-Site, Molecular dynamics simulation, Cytoplasmic Domains, Transmembrane helix 6, Partial Agonists, G-protein binding site, Model, Ligand docking, Activation, Essential dynamics

Turkish CoHE Thesis Center URL

Citation

28

WoS Q

N/A

Scopus Q

N/A

Source

Bmc Structural Biology

Volume

13

Issue

Start Page

End Page