Acta Pharmacologica Sinica最新文献_第2页

Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease. 帕金森病的进行性去甲肾上腺素能退化和运动皮质功能障碍。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-26 DOI: 10.1038/s41401-024-01428-z

Wei Zhou, Hong-Yuan Chu

{"title":"Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease.","authors":"Wei Zhou, Hong-Yuan Chu","doi":"10.1038/s41401-024-01428-z","DOIUrl":"10.1038/s41401-024-01428-z","url":null,"abstract":"The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented in Parkinson's disease (PD). The LC-NE neurodegeneration is believed to underlie various nonmotor symptoms in people with PD, including neuropsychiatric deficits, sleep disruptions, and cognitive impairments. Of particular interest, LC-NE neurons send intensive axonal projections to the motor regions of the cerebral cortex. However, how NE depletion in the motor cortex contributes to PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes in the cerebral cortex as LC-NE degenerates, which might involve its interaction with dopaminergic signaling during the chronic course of the disease. In the present article, we briefly discuss clinical and preclinical studies that support the critical roles of LC-NE neurodegeneration and motor cortical dysfunction in both motor and nonmotor deficits in Parkinsonian states. We focus our discussion on the potential impact of LC-NE neurodegeneration on motor cortical function and the subsequent symptom manifestation. Last, we propose future research directions that can advance our understanding of cortical pathophysiology in PD by integrating noradrenergic degeneration.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"829-835"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer. 新型BCL-2/BCL-XL抑制剂APG-1252介导的GSDME裂解增强了HER2靶向疗法对HER2阳性胃癌的抗肿瘤疗效。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-26 DOI: 10.1038/s41401-024-01414-5

Qiu-Yun Luo, Jing Yang, Tian Di, Zeng-Fei Xia, Lin Zhang, Wen-Tao Pan, Shan Shi, Li-Qiong Yang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang

{"title":"The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer.","authors":"Qiu-Yun Luo, Jing Yang, Tian Di, Zeng-Fei Xia, Lin Zhang, Wen-Tao Pan, Shan Shi, Li-Qiong Yang, Jian Sun, Miao-Zhen Qiu, Da-Jun Yang","doi":"10.1038/s41401-024-01414-5","DOIUrl":"10.1038/s41401-024-01414-5","url":null,"abstract":"HER2-positive gastric cancer has a poor prognosis, with a high incidence of drug resistance and a lack of effective treatments for drug-resistant patients. The exploration of the mechanism of resistance to HER2-targeted therapy in HER2-positive gastric cancer and the identification of effective strategies to reverse it are urgently needed. In this study, we found that HER2-targeted agents upregulated the expression of GSDME and that the overexpression of GSDME attenuated the sensitivity of HER2-targeted agents. Furthermore, we observed that the BCL-2/BCL-XL inhibitor APG-1252 plus lapatinib promoted GSDME-mediated pyroptosis and exhibited remarkable antitumor activity both in vitro and in vivo. Mechanistically, APG-1252 combined with lapatinib synergistically induced GSDME-mediated pyroptosis in HER2-positive gastric cancer by activating caspase-dependent pathways and blocking the phospho-AKT/GSK-3β/MCL-1 signaling pathway. Our data indicated that the combination of lapatinib and APG-1252 had a synergistic antitumor effect on HER2-positive gastric cancer through the induction of caspase-3/GSDME-mediated apoptosis and pyroptosis.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1082-1096"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses. 神经肽介导的星形胶质细胞激活通过调节皮质神经突触改善小鼠的应激恢复能力。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-06 DOI: 10.1038/s41401-024-01420-7

Jing Cui, Xiao-Ran Wang, Jie Yu, Bo-Rui Zhang, Ya-Fei Shi, Kwok-Fai So, Li Zhang, Ji-An Wei

{"title":"Neuropeptide-mediated activation of astrocytes improves stress resilience in mice by modulating cortical neural synapses.","authors":"Jing Cui, Xiao-Ran Wang, Jie Yu, Bo-Rui Zhang, Ya-Fei Shi, Kwok-Fai So, Li Zhang, Ji-An Wei","doi":"10.1038/s41401-024-01420-7","DOIUrl":"10.1038/s41401-024-01420-7","url":null,"abstract":"Astrocytes are known to modulate synaptogenesis or neuronal activities, thus participating in mental functions. It has been shown that astrocytes are involved in the antidepressant mechanism. In this study we investigated the potential hormonal mediator governing the astrocyte-neuron interplay for stress-coping behaviors. Mice were subjected to chronic restraint stress (CRS) for 14 days, and then brain tissue was harvested for analyses. We found that the expression of pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor PAC1 was significantly decreased in astrocytes of the prelimbic (PrL) cortex. By conducting a combination of genetics, in vivo imaging and behavioral assays we demonstrated that PAC1 in cortical astrocytes was necessary for maintaining normal resilience of mice against chronic environmental stress like restraint stress. Furthermore, we showed the enhancement of de novo cortical spine formation and synaptic activity under PACAP-mediated astrocytic activation possibly via the ATP release. The molecular mechanisms suggested that the vesicle homeostasis mediated by PACAP-PAC1 axis in astrocytes was involved in regulating synaptic functions. This study identifies a previously unrecognized route by which neuropeptide modulates cortical functions via local regulation of astrocytes.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"867-879"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia. 一种新的膜联蛋白二聚体靶向星形胶质细胞的小胶质吞噬，以保护脑缺血后的脑血屏障。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-11 DOI: 10.1038/s41401-024-01432-3

Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua

{"title":"A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.","authors":"Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua","doi":"10.1038/s41401-024-01432-3","DOIUrl":"10.1038/s41401-024-01432-3","url":null,"abstract":"Despite the vital role of astrocytes in preserving blood-brain barrier (BBB) integrity, their therapeutic potential as targets in ischemic stroke-induced barrier disruption remains underexplored. We previously reported externalization of phosphatidylserine (PS) on astrocytic membranes concurrent with the emergence of PS externalization in neurons. PS externalization of astrocytes induced microglial phagocytosis of astrocytes, resulting in reduced astrocyte-vascular coupling and subsequent BBB breakdown. Annexin A5 (ANXA5) belongs to the superfamily of calcium (Ca2+)- and phospholipid-binding proteins. Here, we report two X-ray structures of human ANXA5, including monomeric ANXA5 (1.42 Å) and dimeric ANXA5 (1.80 Å). Through the combination of molecular docking and functional analysis, we explored the mechanism of action of ANXA5 in stroke treatment. In addition, we observed a clear increase in therapeutic efficacy corresponding to the increased affinity of ANXA5 for PS. In summary, the phagocytosis of PS-externalized astrocytes by microglia has emerged as a critical mechanism driving BBB breakdown after ischemia. Our findings offer valuable structural insight into ANXA5 as an innovative pharmacological target for safeguarding blood-brain barrier integrity after cerebral ischemia. These insights may facilitate the development of novel PS-targeting medications aimed at achieving enhanced efficacy with minimal side effects.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"852-866"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33. rna结合基序蛋白RBM39通过促进MRPL33的致癌剪接开关来增强胃癌细胞的增殖。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2025-01-03 DOI: 10.1038/s41401-024-01431-4

Cheng-Piao Lu, Jia-Bin Li, Dong-Bao Li, Yu-Hong Wang, Xiao-Gang Jiang, Jing-Jing Ma, Guoqiang Xu

{"title":"RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33.","authors":"Cheng-Piao Lu, Jia-Bin Li, Dong-Bao Li, Yu-Hong Wang, Xiao-Gang Jiang, Jing-Jing Ma, Guoqiang Xu","doi":"10.1038/s41401-024-01431-4","DOIUrl":"10.1038/s41401-024-01431-4","url":null,"abstract":"Gastric cancer is a malignant gastrointestinal disease characterized by high morbidity and mortality rates worldwide. The occurrence and progression of gastric cancer are influenced by various factors, including the abnormal alternative splicing of key genes. Recently, RBM39 has emerged as a tumor biomarker that regulates alternative splicing in several types of cancer. However, the specific functions and key alternative splicing events modulated by RBM39 in gastric cancer are still unclear. In this work, bioinformatic analysis of The Cancer Genome Atlas (TCGA) database and immunoblotting of patient tissue samples revealed that RBM39 was highly expressed in gastric cancer tissues and that its elevated expression significantly reduced overall patient survival. Cell-line-based and tumor xenograft experiments demonstrated that RBM39 knockdown attenuated the growth of gastric cancer cells both in vitro and in vivo. Mechanistically, through RNA-seq, minigene, and RT‒PCR, we discovered and further validated that RBM39 inhibited exon 3 skipping, thereby modulating the splicing of MRPL33. The long isoform MRPL33-L, which includes exon 3, but not the short isoform MRPL33-S, which lacks exon 3, significantly promoted the proliferation and colony formation of gastric cancer cells. Furthermore, we observed an increased percent-splice-in (PSI) of MRPL33 in gastric cancer tissues. Genetic manipulation and pharmacological treatment with the RBM39 degrader indisulam demonstrated that RBM39 regulated cell proliferation by influencing the splicing switch of MRPL33 in gastric cancer cells and a xenograft mouse model. Our findings indicate that RBM39 regulates the oncogenic splicing of MRPL33 and suggest that it may serve as a potential therapeutic target for gastric cancer.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1068-1081"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of Licoflavone C as a cap-dependent endonuclease inhibitor against severe fever with thrombocytopenia syndrome virus.

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 DOI: 10.1038/s41401-025-01533-7

Xiao Gao, Xiao-Xue He, Xue-Rui Zhu, Yan Wu, Jia Lu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan

{"title":"Identification of Licoflavone C as a cap-dependent endonuclease inhibitor against severe fever with thrombocytopenia syndrome virus.","authors":"Xiao Gao, Xiao-Xue He, Xue-Rui Zhu, Yan Wu, Jia Lu, Xin-Lan Chen, Chen-Shu Zhao, Hao-Yu Li, Zhong-Fa Zhang, Shu-Wen Liu, Geng-Fu Xiao, Xiao-Yan Pan","doi":"10.1038/s41401-025-01533-7","DOIUrl":"10.1038/s41401-025-01533-7","url":null,"abstract":"Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with a high fatality rate. Currently no approved drugs or vaccines are available against it. Sharing a common replication mechanism with negative-stranded, segmented viruses (NSVs), SFTSV utilizes a cap-dependent endonuclease (CEN) domain of the L segment to execute the cap-snatching process upon genome transcription initiation. Given the crucial role of CEN in the life cycle of NSVs, it is considered a promising target for discovery of antiviral agents against SFTSV. In this study, we established a high-throughput FRET-based enzymatic screening system to discover inhibitors of SFTSV CEN from a chemical library containing 3467 natural compounds. Finally, three compounds, i.e., Licoflavone C, 3,4-dicaffeoylquinic acid, and oleanolic acid displayed exceptional antiviral effects and minimal cytotoxicity. Licoflavone C (EC50 = 1.85 μM) was selected for further investigation. Administration of Licoflavone C (20 mg/kg, i.v.) significantly reduced tissue viral loads in SFTSV-challenged mouse model. We demonstrated that Licoflavone C did not directly bind to the active pocket of SFTSV CEN but disrupted its active conformation, resulting in substrate non-competitive inhibition. Licoflavone C also exhibited broad-spectrum inhibition on several NSV CENs (HRTV, GTV, and LCMV) besides SFTSV. Furthermore, 15 analogs of Licoflavone C sharing a typical flavonoid structure were verified for targeting SFTSV CEN and exhibiting antiviral activities. In conclusion, Licoflavone C is a promising inhibitor of SFTSV, offering insights into targeting CEN with flavonoids in drug discovery.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells. 抑制hif -脯氨酸羟化酶通过肾近端小管细胞重编程促进肾小管再生。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2025-01-07 DOI: 10.1038/s41401-024-01445-y

Jing Li, Li-Ting Chen, You-Liang Wang, Mei-Xia Kang, Shi-Ting Liang, Xi-Zhen Hong, Fan Fan Hou, Fu-Jian Zhang

{"title":"Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells.","authors":"Jing Li, Li-Ting Chen, You-Liang Wang, Mei-Xia Kang, Shi-Ting Liang, Xi-Zhen Hong, Fan Fan Hou, Fu-Jian Zhang","doi":"10.1038/s41401-024-01445-y","DOIUrl":"10.1038/s41401-024-01445-y","url":null,"abstract":"The ability of the mammalian kidney to repair or regenerate after acute kidney injury (AKI) is very limited. The maladaptive repair of AKI promotes progression to chronic kidney disease (CKD). Therefore, new strategies to promote the repair/regeneration of injured renal tubules after AKI are urgently needed. Hypoxia has been shown to induce heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxic conditions and found that MK-8617 significantly ameliorated ischemia reperfusion injury (IRI)-induced AKI. We also showed that MK-8617 dramatically facilitated renal tubule regeneration by promoting the proliferation of renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis-related genes were significantly upregulated with MK-8617 pretreatment. We also showed that MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells. Furthermore, we demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells and the regeneration of renal proximal tubules. In summary, we report that the inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI by promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1002-1015"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling. Smad 转录因子是 7 跨膜 G 蛋白偶联受体信号的媒介。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-06 DOI: 10.1038/s41401-024-01413-6

Zheng-Jie Chia, Hirushi Kumarapperuma, Ruizhi Zhang, Peter J Little, Danielle Kamato

{"title":"Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling.","authors":"Zheng-Jie Chia, Hirushi Kumarapperuma, Ruizhi Zhang, Peter J Little, Danielle Kamato","doi":"10.1038/s41401-024-01413-6","DOIUrl":"10.1038/s41401-024-01413-6","url":null,"abstract":"The Smad transcription factors are well known for their role at the core of transforming growth factor-β (TGF-β) signalling. However, recent evidence shows that the Smad transcription factors play a vital role downstream of other classes of receptors including G protein-coupled receptors (GPCR). The versatility of Smad transcription factors originated from the two regions that can be differently activated by the TGF-β receptor superfamily or through the recruitment of intracellular kinases stimulated by other receptors classes such as GPCRs. The classic GPCR signalling cascade is further expanded to conditional adoption of the Smad transcription factor under the stimulation of Akt, demonstrating the unique involvement of the Smad transcription factor in GPCR signalling pathways in disease environments. In this review, we provide a summary of the signalling pathways of the Smad transcription factors as an important downstream mediator of GPCRs, presenting exciting opportunities for discovering new therapeutic targets for diseases.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"795-804"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential. 针对神经退行性疾病中伴侣介导的自噬：机制和治疗潜力。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-11-15 DOI: 10.1038/s41401-024-01416-3

Jin Wu, Wan Xu, Ying Su, Guang-Hui Wang, Jing-Jing Ma

引用次数: 0

AlphaFold3 versus experimental structures: assessment of the accuracy in ligand-bound G protein-coupled receptors. AlphaFold3与实验结构：评估配体结合G蛋白偶联受体的准确性。

IF 6.9 1区医学

Acta Pharmacologica Sinica Pub Date : 2025-04-01 Epub Date: 2024-12-06 DOI: 10.1038/s41401-024-01429-y

Xin-Heng He, Jun-Rui Li, Shi-Yi Shen, H Eric Xu

{"title":"AlphaFold3 versus experimental structures: assessment of the accuracy in ligand-bound G protein-coupled receptors.","authors":"Xin-Heng He, Jun-Rui Li, Shi-Yi Shen, H Eric Xu","doi":"10.1038/s41401-024-01429-y","DOIUrl":"10.1038/s41401-024-01429-y","url":null,"abstract":"G protein-coupled receptors (GPCRs) are critical drug targets involved in numerous physiological processes, yet many of their structures remain unresolved due to inherent flexibility and diverse ligand interactions. This study systematically evaluates the accuracy of AlphaFold3-predicted GPCR structures compared to experimentally determined structures, with a primary focus on ligand-bound states. Our analysis reveals that while AlphaFold3 shows improved performance over AlphaFold2 in predicting overall GPCR backbone architecture, significant discrepancies persist in ligand-binding poses, particularly for ions, peptides, and proteins. Despite advancements, these limitations constrain the utility of AlphaFold3 models in functional studies and structure-based drug design, where high-resolution details of ligand interactions are crucial. We assess the accuracy of predicted structures across various ligand types, quantifying deviations in binding pocket geometries and ligand orientations. Our findings highlight specific challenges in the computational prediction of ligand-bound GPCR structures, emphasizing areas where further refinement is needed. This study provides valuable insights for researchers using AlphaFold3 in GPCR studies, underscores the ongoing necessity for experimental structure determination, and offers direction for improving protein-ligand interaction predictions in future computational models.","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"1111-1122"},"PeriodicalIF":6.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0