Structural basis of GPBAR activation and bile acid recognition

Yang, Fan; Mao, Chunyou; Guo, Lulu; Lin, Jing‐Yu; Ming, Qianqian; Peng, Xiao; Wu, Xiang; Shen, Qingya; Guo, Shimeng; Shen, Dan‐Dan; Lu, Ruirui; Zhang, Linqi; Huang, Shuai; Ping, Yu; Zhang, Chenlu; Ma, Cheng; Zhang, Kai; Liang, Xiaoying; Shen, Yuemao; Nan, Fa‐Jun; Yi, Fan; Luca, Vincent C.; Zhou, Jiuyao; Jiang, Changtao; Sun, Junying; Xie, Xin; Yu, Xiao; Zhang, Yan

doi:10.1038/s41586-020-2569-1

Cited by 107 publications

(67 citation statements)

References 36 publications

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“…6 A) [111] . In the structural analysis of the complex, INT-777 interacts with F96 and Y240 at the bottom of the orthosteric site of GPBAR1 [111] . OCA is an FXR agonist and shows a high binding affinity for GPBAR1.…”

Section: Ligand-binding Properties Of Fxrmentioning

confidence: 99%

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Farnesoid X receptor (FXR): Structures and ligands

Jiang

Zhang

Xiao

et al. 2021

Computational and Structural Biotechnology Journal

103

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Section: Ligand-binding Properties Of Fxrmentioning

confidence: 99%

“…Yang et al recently reported the structure of the INT-777/GPBAR GS complex, which provides the structural basis for GPBAR1 activation and bile acid recognition ( Fig. 6 A) [111] . In the structural analysis of the complex, INT-777 interacts with F96 and Y240 at the bottom of the orthosteric site of GPBAR1 [111] .…”

Section: Ligand-binding Properties Of Fxrmentioning

confidence: 99%

Farnesoid X receptor (FXR): Structures and ligands

Jiang

Zhang

Xiao

et al. 2021

Computational and Structural Biotechnology Journal

103

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“…2d). Structures of several GPCRs with sterol ligands, such as Smoothened 39 and the bile acid receptor GPBAR 40 have been reported. The sterol ligands in these GPCRs insert into the transmembrane domain perpendicularly to the membrane, in contrast to the binding pose of DHF, which is almost parallel to the membrane.…”

Section: Resultsmentioning

confidence: 99%

Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

et al. 2020

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Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations in the SRD5A2 gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride, as SRD5A2 inhibitors, are widely used antiandrogen drugs for benign prostate hyperplasia. The molecular mechanisms underlying enzyme catalysis and inhibition for SRD5A2 and other eukaryotic integral membrane steroid reductases remain elusive due to a lack of structural information. Here, we report a crystal structure of human SRD5A2 at 2.8 Å, revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the transmembrane domain. Structural analysis together with computational and mutagenesis studies reveal the molecular mechanisms of the catalyzed reaction and of finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region that regulate NADPH/NADP+ exchange. Mapping disease-causing mutations of SRD5A2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and may facilitate drug development.

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“…The beta2-adrenoceptor (β2-AR) is a canonical GPCR, the canonical GPCR beta2-adrenoceptor (β2-AR) is internalized, ubiquitinated and nally degraded after being stimulated with agonist, and also results in increase of cAMP levels [46]. Yang et al [47] demonstrated that activation of TGR5 with TGR5 agonist resulted in structure change of TGR5. Ligand binding to several mammalian G protein-coupled receptors, such as the PTHR, results in conformational changes and receptor internalization [48].…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic Acid Suppresses The Malignant Progression of Colorectal Cancer Through TGR5-YAP Axis

Zhang

et al. 2021

Preprint

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Background: The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. The study means to explore relationship of UDCA and YAP in CRC.Methods: The effect of UDCA on CRC cells proliferation was examined by MTT and clonogenic assay, western blotting (WB), real-time PCR, seperation of nucleoprotein and cytoplasmic protein and immunofluorescence (IF) assays were used to detect expression of YAP, WB, real-time PCR, GST-pull down assay and rhodamine-labeled phalloidin staining assays were used to detect activity of RhoA. After transfection of YAP5SA plasmids and RhoAV14 plasmids respectively, MTT, clonogenic assay, EdU incorporation assays and WB were performed. WB and ELISA were used to detect activity of cAMP/PKA axis, after blocking cAMP/PKA axis with siRNA and inhibitors, MTT, WB, IF and clonogenic assay were performed to test effect of UDCA on CRC cells. WB, IF and real-time PCR assays were used to detect expression of TGR5 in CRC cells after UDCA treatment, and then TGR5 agonist, TGR5 antagonist and siRNA were used to detect effect of UDCA on CRC cells. AOM/DSS-induced primary model was used to detect effect of UDCA, WB and Immunohistochemistry (IHC) were used to detect expression of related proteins.Results: UDCA suppressed YAP signaling by activating the membrane G‐protein‐coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67.Conclusion: UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.

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Structural basis of GPBAR activation and bile acid recognition

Cited by 107 publications

References 36 publications

Farnesoid X receptor (FXR): Structures and ligands

Farnesoid X receptor (FXR): Structures and ligands

Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride

Ursodeoxycholic Acid Suppresses The Malignant Progression of Colorectal Cancer Through TGR5-YAP Axis

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