Effect of intracellular loop 3 on intrinsic dynamics of human β2-adrenergic receptorReport as inadecuate

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BMC Structural Biology

, 13:29

Computational analysis


BackgroundTo understand the effect of the long intracellular loop 3 ICL3 on the intrinsic dynamics of human β2-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 μs molecular dynamics MD simulation at 310 K.

ResultsAfter 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 Å from 11 Å, which was further elaborated by docking studies.

ConclusionsThe 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.

KeywordsICL3 Molecular dynamics simulation Transmembrane helix 6 G-protein binding site Ligand docking Essential dynamics AbbreviationsGPCRsG protein coupled receptors

β2ARβ2-adrenergic receptor

ICLIntracellular loop


MDMolecular dynamics


TMEMBTransmembrane region

RMSDRoot mean square deviation

RMSFRoot mean square fluctuation

ECLExtracellular loop

TMTransmembrane helix

PCAPrincipal component analysis

ANMAnisotropic network model.

Electronic supplementary materialThe online version of this article doi:10.1186-1472-6807-13-29 contains supplementary material, which is available to authorized users.

Ozer Ozcan, Arzu Uyar contributed equally to this work.

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Author: Ozer Ozcan - Arzu Uyar - Pemra Doruker - Ebru Demet Akten

Source: https://link.springer.com/


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