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Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
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2015 (English)In: Scientific Reports, ISSN 2045-2322, Vol. 5, 8066- p.Article in journal (Refereed) Published
Abstract [en]

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

Place, publisher, year, edition, pages
2015. Vol. 5, 8066- p.
Keyword [en]
Protein-Coupled Receptors, Beta(2)-Adrenergic Receptor, Molecular-Dynamics, Conformations, Pharmacology, Sensitivity, Activation, Kinetics, Pathway
National Category
Biological Sciences Chemical Sciences
URN: urn:nbn:se:kth:diva-160743DOI: 10.1038/srep08066ISI: 000348435800001PubMedID: 25628267OAI: diva2:791887
Swedish National Infrastructure for Computing (SNIC), SNIC2013-26-31 SNIC2013-1-236

QC 20150302

Available from: 2015-03-02 Created: 2015-02-27 Last updated: 2015-05-20Bibliographically approved
In thesis
1. Theoretical Studies of G-Protein-Coupled Receptors
Open this publication in new window or tab >>Theoretical Studies of G-Protein-Coupled Receptors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The family of G-protein-coupled receptors (GPCRs) contains the largest number of drug targets in the human body, with more than a quarter of the clinically used drugs targeting them. Because of the important roles GPCRs play in the human body, the mechanisms of activation of GPCRs or ligands binding to GPCRs have captivated much research interest since the discovery of GPCRs. A number of GPCR crystal structures determined in recent years have provided us with unprecedented opportunities in investigating how GPCRs function through the conformational changes regulated by their ligands. This has motivated me to perform molecular dynamics (MD) simulations in combination with a variety of other modeling methods to study the activation of some GPCRs and their ligand selectivity.

This thesis consists of six chapters. In the first chapter, a brief introduction of GPCRs and MD simulation techniques is given. Detailed MD simulation techniques, including pressure controlling methods and temperature coupling approaches, are described in chapter 2. The metadynamics simulation technique, used to enhance conformational sampling, is described in chapter 3. In chapter 4, I outline the inhomogeneous fluid theory used to calculate the thermodynamics properties of interfacial water molecules. Using the methods described in chapters 2-4, I carried out theoretical investigations on some GPCRs with the results summarized in chapter 5. In chapter 6, I provide a summary of the thesis with future work outlined in an outlook. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. viii, 60 p.
TRITA-BIO-Report, ISSN 1654-2312 ; 2015:13
National Category
Biological Sciences
Research subject
Biological Physics
urn:nbn:se:kth:diva-166407 (URN)978-91-7595-589-6 (ISBN)
Public defence
2015-06-03, FD5 AlbaNova, Roslagstullsbacken, KTH, Stockholm, 10:00 (English)

QC 201505020

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved

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