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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

(a) The RMSD values of the ligand with respect to the first snapshots of the simulations; (b) The distance between the side chain of Asn5.50 and the nitrogen on the pyridine ring of CP-376395; (c) The distance between the backbone carbon atoms on Tyr6.63 and His2283.40 (CRF1R) or between the backbone carbon atoms on Tyr6.63 and Val2283.40 (CRF2R); (d) The distance between the side chain oxygen atoms on Tyr6.63 and Gln5.50; (e) Cross-section view of CRF1R with the bottleneck formed; (f) Cross-section view of CRF2R without the bottleneck. In (e) and (f), the antagonist binding pockets are colored in magenta.
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f4: (a) The RMSD values of the ligand with respect to the first snapshots of the simulations; (b) The distance between the side chain of Asn5.50 and the nitrogen on the pyridine ring of CP-376395; (c) The distance between the backbone carbon atoms on Tyr6.63 and His2283.40 (CRF1R) or between the backbone carbon atoms on Tyr6.63 and Val2283.40 (CRF2R); (d) The distance between the side chain oxygen atoms on Tyr6.63 and Gln5.50; (e) Cross-section view of CRF1R with the bottleneck formed; (f) Cross-section view of CRF2R without the bottleneck. In (e) and (f), the antagonist binding pockets are colored in magenta.

Mentions: CP-376395 binds to an unexpected site located in the cytoplasmic half of the receptor CRF1R, which is about 18 Å away from the putative agonist binding site of the receptor and is about 13–23 Å away from the corresponding small ligand binding site of family A GPCRs16. Consistent with the observation of Bai et al., small RMSD values (~0.5 Å) of the ligand were obtained from our simulation of CRF1R. In contrast, CP-376395 shows RMSD values in the binding pocket of CRF2R larger than in that of CRF1R as indicated in Figure 4a. The conserved residue Asn5.50 forms an essential hydrogen bond with the nitrogen on the pyridine ring of CP-376395 and mutation of this residue to Ala results in a complete loss of ligand binding1. This key hydrogen bond is preserved during the simulations of both CRF1R and CRF2R and stabilizes the aryloxy moiety of CP-376395 (Figure 4b). Thus, the larger RMSD value of CP-376395 in CRF2R is mainly contributed by the fluctuation of the exocyclic alkylamino group.


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)

(a) The RMSD values of the ligand with respect to the first snapshots of the simulations; (b) The distance between the side chain of Asn5.50 and the nitrogen on the pyridine ring of CP-376395; (c) The distance between the backbone carbon atoms on Tyr6.63 and His2283.40 (CRF1R) or between the backbone carbon atoms on Tyr6.63 and Val2283.40 (CRF2R); (d) The distance between the side chain oxygen atoms on Tyr6.63 and Gln5.50; (e) Cross-section view of CRF1R with the bottleneck formed; (f) Cross-section view of CRF2R without the bottleneck. In (e) and (f), the antagonist binding pockets are colored in magenta.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: (a) The RMSD values of the ligand with respect to the first snapshots of the simulations; (b) The distance between the side chain of Asn5.50 and the nitrogen on the pyridine ring of CP-376395; (c) The distance between the backbone carbon atoms on Tyr6.63 and His2283.40 (CRF1R) or between the backbone carbon atoms on Tyr6.63 and Val2283.40 (CRF2R); (d) The distance between the side chain oxygen atoms on Tyr6.63 and Gln5.50; (e) Cross-section view of CRF1R with the bottleneck formed; (f) Cross-section view of CRF2R without the bottleneck. In (e) and (f), the antagonist binding pockets are colored in magenta.
Mentions: CP-376395 binds to an unexpected site located in the cytoplasmic half of the receptor CRF1R, which is about 18 Å away from the putative agonist binding site of the receptor and is about 13–23 Å away from the corresponding small ligand binding site of family A GPCRs16. Consistent with the observation of Bai et al., small RMSD values (~0.5 Å) of the ligand were obtained from our simulation of CRF1R. In contrast, CP-376395 shows RMSD values in the binding pocket of CRF2R larger than in that of CRF1R as indicated in Figure 4a. The conserved residue Asn5.50 forms an essential hydrogen bond with the nitrogen on the pyridine ring of CP-376395 and mutation of this residue to Ala results in a complete loss of ligand binding1. This key hydrogen bond is preserved during the simulations of both CRF1R and CRF2R and stabilizes the aryloxy moiety of CP-376395 (Figure 4b). Thus, the larger RMSD value of CP-376395 in CRF2R is mainly contributed by the fluctuation of the exocyclic alkylamino group.

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