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Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 18913Article in journal (Refereed) PublishedText
Abstract [en]

The κ opioid receptor (κOR) is a member of G-protein-coupled receptors, and is considered as a promising drug target for treating neurological diseases. κOR selective 6′-GNTI was proved to be a G-protein biased agonist, whereas 5′-GNTI acts as an antagonist. To investigate the molecular mechanism of how these two ligands induce different behaviors of the receptor, we built two systems containing the 5′-GNTI-κOR complex and the 6′-GNTI-κOR complex, respectively, and performed molecular dynamics simulations of the two systems. We observe that transmembrane (TM) helix 6 of the κOR rotates about 4.6° on average in the κOR-6′-GNTI complex. Detailed analyses of the simulation results indicate that E2976.58 and I2946.55 play crucial roles in the rotation of TM6. In the simulation of the κOR-5′-GNTI system, it is revealed that 5′-GNTI can stabilize TM6 in the inactive state form. In addition, the kink of TM7 is stabilized by a hydrogen bond between S3247.47 and the residue V691.42 on TM1.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016. Vol. 6, 18913
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URN: urn:nbn:se:kth:diva-181442DOI: 10.1038/srep18913ISI: 000368677900001PubMedID: 26742690ScopusID: 2-s2.0-84953897601OAI: diva2:900389
Swedish National Infrastructure for Computing (SNIC), SNIC2014-11-31Swedish National Infrastructure for Computing (SNIC), SNIC2014-1-326

QC 20160204. QC 20160218

Available from: 2016-02-04 Created: 2016-02-02 Last updated: 2016-02-18Bibliographically approved

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Sun, XianqiangTu, Yaoquan
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