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Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1.

Sun X, Cheng J, Wang X, Tang Y, Ågren H, Tu Y - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

The crystal structure of CRF1R and the modeled structure of CRF2R.The protein structures are shown in the cartoon mode and the antagonist CP-376395 is shown in the stick mode. The structures of CRF1R and CRF2R are colored in green and cyan, respectively. The antagonist CP-376395 is colored in yellow. (a) Alignment of the crystal structure of CRF1R and the modeled structure of CRF2R; (b) Key residues in the antagonist binding pocket of CRF1R; (c) Key residues in the antagonist binding pocket of CRF2R.
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f1: The crystal structure of CRF1R and the modeled structure of CRF2R.The protein structures are shown in the cartoon mode and the antagonist CP-376395 is shown in the stick mode. The structures of CRF1R and CRF2R are colored in green and cyan, respectively. The antagonist CP-376395 is colored in yellow. (a) Alignment of the crystal structure of CRF1R and the modeled structure of CRF2R; (b) Key residues in the antagonist binding pocket of CRF1R; (c) Key residues in the antagonist binding pocket of CRF2R.

Mentions: CRF1R and CRF2R belong to the same family and share a high sequence identity. The identity rate is 73% if only the transmembrane parts of the receptors are considered. The sequence alignment of CRF2R to CRF1R is shown in Figure S1. We can see that the most conserved residues match each other (Table S1). A Richardson plot of the modeled CRF2R structure indicates that 98% of the residues are located in the allowed regions, reflecting that the structure is geometrically reasonable (Figure S2)12. The root mean square deviation (RMSD) between the crystal structure of CRF1R and the modeled structure of CRF2R is 0.01 Å (Figure 1).


Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1.

Sun X, Cheng J, Wang X, Tang Y, Ågren H, Tu Y - Sci Rep (2015)

The crystal structure of CRF1R and the modeled structure of CRF2R.The protein structures are shown in the cartoon mode and the antagonist CP-376395 is shown in the stick mode. The structures of CRF1R and CRF2R are colored in green and cyan, respectively. The antagonist CP-376395 is colored in yellow. (a) Alignment of the crystal structure of CRF1R and the modeled structure of CRF2R; (b) Key residues in the antagonist binding pocket of CRF1R; (c) Key residues in the antagonist binding pocket of CRF2R.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308710&req=5

f1: The crystal structure of CRF1R and the modeled structure of CRF2R.The protein structures are shown in the cartoon mode and the antagonist CP-376395 is shown in the stick mode. The structures of CRF1R and CRF2R are colored in green and cyan, respectively. The antagonist CP-376395 is colored in yellow. (a) Alignment of the crystal structure of CRF1R and the modeled structure of CRF2R; (b) Key residues in the antagonist binding pocket of CRF1R; (c) Key residues in the antagonist binding pocket of CRF2R.
Mentions: CRF1R and CRF2R belong to the same family and share a high sequence identity. The identity rate is 73% if only the transmembrane parts of the receptors are considered. The sequence alignment of CRF2R to CRF1R is shown in Figure S1. We can see that the most conserved residues match each other (Table S1). A Richardson plot of the modeled CRF2R structure indicates that 98% of the residues are located in the allowed regions, reflecting that the structure is geometrically reasonable (Figure S2)12. The root mean square deviation (RMSD) between the crystal structure of CRF1R and the modeled structure of CRF2R is 0.01 Å (Figure 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus