ArticleScientific reports2015
Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Who cites it
6 citing papers in PubMed, 20 citations in OpenAlex.
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- Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.Structure (London, England : 1993) · 2016Article
- Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis.Scientific reports · 2016Article
- Computational studies of the binding profile of phosphoinositide PtdIns (3,4,5) P₃ with the pleckstrin homology domain of an oomycete cellulose synthase.Scientific reports · 2016Article
- Molecular switches of the κ opioid receptor triggered by 6'-GNTI and 5'-GNTI.Scientific reports · 2016Article
- Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.PLoS computational biology · 2016Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.