Dataset Information

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

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.

SUBMITTER: Sun X

PROVIDER: S-EPMC4308710 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Sun Xianqiang X Cheng Jianxin J Wang Xu X Tang Yun Y Ågren Hans H Tu Yaoquan Y

Scientific reports 20150128

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 t ...[more]

PMID: 25628267

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Project description:ObjectiveGenetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.MethodThe test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.ResultsThe authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.ConclusionsThese findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

Dataset Information

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

Publications

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

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