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New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect.

ABSTRACT: INTRODUCTION:Androgen Receptor (AR) plays a pivotal role in the development of male sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain (LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth. METHODS:To find out the interaction mechanisms of BUD31 with WT/T877A/W741L AR complex, molecular dynamics simulations were employed to study the complex BUD31 and WT/mutant ARs. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) results demonstrated that T877A and W741L point mutations can reduce the binding affinity between BUD31 and AR. The RMSF and dynamic cross-correlation analysis indicated that amino acid point mutations can affect the motions of loop residues in the AR structure. RESULTS:These results indicated that AR co-regulator binding site AF2 can serve as a target for drug discovery to solve the resistance problem.

SUBMITTER: Song T

PROVIDER: S-EPMC6967182 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect.

Song Tianqing T Li Jiazhong J

Current computer-aided drug design 20200101 1

<h4>Introduction</h4>Androgen Receptor (AR) plays a pivotal role in the development of male sex and contributes to prostate cancer growth. Different from other nuclear receptors that bind to the co-regulator LxxLL motif in coregulator peptide interaction, the AR Ligand Binding Domain (LBD) prefers to bind to the FxxLF motif. BUD31, a novel co-regulator with FxxLF motif, has been demonstrated to suppress wild-type and mutated AR-mediated prostate cancer growth.<h4>Methods</h4>To find out the inte ...[more]

PMID: 31057123

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Project description:BackgroundAndrogen receptor (AR) splice variants (AR-Vs) have been discussed as a biomarker in prostate cancer (PC). However, some reports question the predictive property of AR-Vs. From a mechanistic perspective, the connection between AR full length (AR-FL) and AR-Vs is not fully understood. Here, we aimed to investigate the dependence of AR-FL and AR-V expression levels on AR gene activity. Additionally, we intended to comprehensively analyze presence of AR-FL and three clinically relevant AR-Vs (AR-V3, AR-V7 and AR-V9) in different stages of disease, especially with respect to clinical utility in PC patients undergoing AR targeted agent (ARTA) treatment.MethodsAR-FL and AR-V levels were analyzed in PC and non-PC cell lines upon artificial increase of AR pre-mRNA using either drug treatment or AR gene activation. Furthermore, expression of AR-FL and AR-Vs was determined in PC specimen at distinct stages of disease (primary (n = 10) and metastatic tissues (n = 20), liquid biopsy samples (n = 422), mCRPC liquid biopsy samples of n = 96 patients starting novel treatment). Finally, baseline AR-FL and AR-V status was correlated with clinical outcome in a defined cohort of n = 65 mCRPC patients undergoing ARTA treatment.ResultsWe revealed rising levels of AR-FL accompanied with appearance and increase of AR-Vs in dependence of elevated AR pre-mRNA levels. We also noticed increase in AR-FL and AR-V levels throughout disease progression. AR-V expression was always associated with high AR-FL levels without any sample being solely AR-V positive. In patients undergoing ARTA treatment, AR-FL did show prognostic, yet not predictive validity. Additionally, we observed a substantial clinical response to ARTA treatment even in AR-V positive patients. Accordingly, multivariate analysis did not demonstrate independent significance of AR-Vs in neither predictive nor prognostic clinical utility.ConclusionWe demonstrate a correlation between AR-FL and AR-V expression during PC progression; with AR-V expression being a side-effect of elevated AR pre-mRNA levels. Clinically, AR-V positivity relies on high levels of AR-FL, making cells still vulnerable to ARTA treatment, as demonstrated by AR-FL and AR-V positive patients responding to ARTA treatment. Thus, AR-FL and AR-V might be considered as a prognostic, yet not predictive biomarker in mCRPC patients.

Project description:ContextOnly approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene.ObjectiveThe objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.DesignQuantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus.SettingThe study was conducted at a university hospital endocrine research laboratory.PatientsGFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46).Intervention(s)There were no interventions.Main outcome measure(s)DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured.ResultsThe APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling.ConclusionsAR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

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New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect.

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New Insights into the Binding Mechanism of Co-regulator BUD31 to AR AF2 Site: Structural Determination and Analysis of the Mutation Effect.

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