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1,056 results on '"Xu, H. Eric"'

40. Development of highly potent glucocorticoids for steroid-resistant severe asthma

Author

He, Yuanzheng, Shi, Jingjing, Nguyen, Quang Tam, You, Erli, Liu, Hongbo, Ren, Xin, Wu, Zhongshan, Li, Jianshuang, Qiu, Wenli, Khoo, Sok Kean, Yang, Tao, Yi, Wei, Sun, Feng, Xi, Zhijian, Huang, Xiaozhu, Melcher, Karsten, Min, Booki, and Xu, H Eric

Subjects
Lung, Asthma, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Respiratory, Animals, Anti-Asthmatic Agents, Disease Models, Animal, Drug Development, Female, Glucocorticoids, Male, Mice, Receptors, Glucocorticoid, Severity of Illness Index, steroid resistant asthma, glucocorticoid, high potency, VSG158, VSG159, steroid-resistant asthma
Abstract

Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.

Published
2019

41. Structural basis for the tethered peptide activation of adhesion GPCRs

Author

Ping, Yu-Qi, Xiao, Peng, Yang, Fan, Zhao, Ru-Jia, Guo, Sheng-Chao, Yan, Xu, Wu, Xiang, Zhang, Chao, Lu, Yan, Zhao, Fenghui, Zhou, Fulai, Xi, Yue-Tong, Yin, Wanchao, Liu, Feng-Zhen, He, Dong-Fang, Zhang, Dao-Lai, Zhu, Zhong-Liang, Jiang, Yi, Du, Lutao, Feng, Shi-Qing, Schöneberg, Torsten, Liebscher, Ines, Xu, H. Eric, and Sun, Jin-Peng

Published
2022
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42. Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3.

Author

Yujue Wang, Youwei Xu, Yue Wang, Jie Zhang, Lan Chen, Xinheng He, Wenjia Fan, Kai Wu, Wen Hu, Xi Cheng, Guizhu Yang, Xu, H. Eric, Youwen Zhuang, and Shuyang Sun

Subjects
SOMATOSTATIN receptors, LIGAND binding (Biochemistry), LIGANDS (Biochemistry), NEUROENDOCRINE tumors, SMALL molecules
Abstract

Somatostatin receptors (SSTRs) exert critical biological functions such as negatively regulating hormone release and cell proliferation, making them popular targets for developing therapeutics to treat endocrine disorders, especially neuroendocrine tumors. Although several panagonists mimicking the endogenous ligand somatostatin are available, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and regulation of divergent SSTR subtypes. Here, we report four cryoelectron microscopy structures of Gi-coupled SSTR1 and SSTR3 activated by distinct agonists, including the FDA-approved panagonist pasireotide as well as their selective small molecule agonists L-797591 and L-796778. Our structures reveal a conserved recognition pattern of pasireotide in SSTRs attributed to the binding with a conserved extended binding pocket, distinct from SST14, octreotide, and lanreotide. Together with mutagenesis analyses, our structures further reveal the dynamic feature of ligand binding pockets in SSTR1 and SSTR3 to accommodate divergent agonists, the key determinants of ligand selectivity lying across the orthosteric pocket of different SSTR subtypes, as well as the molecular mechanism underlying diversity and conservation of receptor activation. Our work provides a framework for rational design of subtype-selective SSTR ligands and may facilitate drug development efforts targeting SSTRs with improved therapeutic efficacy and reduced side effects. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Conformational heterogeneity of the allosteric drug and metabolite (ADaM) site in AMP-activated protein kinase (AMPK).

Author

Gu, Xin, Bridges, Michael D, Yan, Yan, de Waal, Parker W, Zhou, X Edward, Suino-Powell, Kelly M, Xu, H Eric, Hubbell, Wayne L, and Melcher, Karsten

Subjects
Humans, Benzoates, Benzimidazoles, Adenosine Monophosphate, Ligands, Crystallography, X-Ray, Allosteric Regulation, Binding Sites, Catalytic Domain, Protein Conformation, AMP-Activated Protein Kinases, Protein Domains, ADaM site, AMP-activated kinase, DEER, biophysics, cancer, diabetes, metabolic regulation, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the α-subunit and the carbohydrate-binding module (CBM) in the β-subunit. Here, using double electron-electron resonance (DEER) spectroscopy, we demonstrate that the CBM-KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD-CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD-CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals.

Published
2018

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