Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor

Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{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 carazol...
Ausführliche Beschreibung

Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{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 μs 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 Å from 11 Å, 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. Ausführliche Beschreibung

Autor*in:	Ozcan, Ozer [verfasserIn] Uyar, Arzu Doruker, Pemra Akten, Ebru Demet

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2013

Schlagwörter:	ICL3 Molecular dynamics simulation Transmembrane helix 6 G-protein binding site Ligand docking Essential dynamics

Anmerkung:	© Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (

Übergeordnetes Werk:	Enthalten in: BMC structural biology - London : BioMed Central, 2001, 13(2013), 1 vom: 09. Nov.
Übergeordnetes Werk:	volume:13 ; year:2013 ; number:1 ; day:09 ; month:11

Links:	Volltext

DOI / URN:	10.1186/1472-6807-13-29

Katalog-ID:	SPR02862968X