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23 results on '"Chu, Hsing‐Mao"'

6. A bispecific antibody binding to RANKL and osteonectin with enhanced localization to the bone

Author

Chen, Jou-Han, Lin, Chun Yu, Chen, Yi-Chun Maria, Tian, Wei-Ting, Chu, Hsing-Mao, and Chang, Tse Wen

Abstract

Therapeutics reducing bone turnover, such as denosumab (Dmab), an anti-RANKL antibody, can provide treatments for patients with bone destruction. However, some patients with osteoporosis or localized primary bone tumors and many patients with various types of bone-metastatic cancer display unsatisfactory responses to Dmab. For achieving greater efficiency of RANKL neutralization in the bone microenvironment by enhancing the distribution of Dmab to the bone, we reengineered Dmab by fusing with single-chain variable fragments of an antibody specific for osteonectin (On), which is abundantly expressed in osseous tissues. The bispecific antibody, Dmab-FvOn, showed a similar activity as Dmab in inhibiting RANKL as examined in an osteoclast differentiation assay. When administered to mice, Dmab-FvOn was found to localize in increased proportions at the endosteum of the bone where osteonectin is abundant. Our study suggests that by linking anti-RANKL with an osteonectin-targeting moiety, a greater proportion of the therapeutic effector can be distributed in the bone. Future studies are needed to investigate whether the bispecific antibody can achieve higher therapeutic efficacy and lower toxicity.

Published
2024
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21. Cystei ne S-N itrosylation Protects Protein-tyrosine Phosphatase 1B against Oxidation-induced Permanent Inactivation.

Author

Chen, Yi-Yun, Chu, Hsing-Mao, Pan, Kuan-Ting, Teng, Chun-Hung, Wang, Danny-Ling, Wang, Andrew H.-J., Khoo, Kay-Hooi, and Meng, Tzu-Ching

Subjects
*PROTEINS, *PHOSPHATASES, *OXIDATION, *NITRIC oxide, *REACTIVE oxygen species, *MASS spectrometry
Abstract

Protein S-nitrosylation mediated by cellular nitric oxide (NO) plays a primary role in executing biological functions in cGMP- independent NO signaling. Although S-nitrosylation appears similar to Cys oxidation induced by reactive oxygen species, the molecular mechanism and biological consequence remain unclear. We investigated the structural process of S-nitrosylation of protein-tyrosine phosphatase lB (PTP1B). We treated PTP1B with various NO donors, including S-nitrosothiol reagents and compound-releasing NO radicals, to produce site-specific Cys S-nitrosylation identified using advanced mass spectrometry (MS) techniques. Quantitative MS showed that the active site Cys-215 was the primary residue susceptible to S-nitrosylation. The crystal structure of NO donor-reacted PTP1B at 2.6 A resolution revealed that the S-NO state at Cys-215 had no discernible irreversibly oxidized forms, whereas other Cys residues remained in their free thiol states. We further demonstrated that S-nitrosylation of the Cys-215 residue pro- tected PTP1B from subsequent H202-induced irreversible oxidation. Increasing the level of cellular NO by pretreating cells with an NO donor or by activating ectopically expressed NO synthase inhibited reactive oxygen species-induced irreversible oxidation of endogenous PTP1B. These findings suggest that S-nitrosylation might prevent PTPs from permanent inactivation caused by oxidative stress. [ABSTRACT FROM AUTHOR]

Published
2008
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22. Structures of Selenomonas ruminantium Phytase in Complex with Persulfated Phytate DSP Phytase Fold and Mechanism for Sequential Substrate Hydrolysis

Author

Chu, Hsing-Mao, Guo, Rey-Ting, Lin, Ting-Wan, Chou, Chia-Cheng, Shr, Hui-Lin, Lai, Hui-Lin, Tang, Tsung-Yin, Cheng, Kuo-Joan, Selinger, Brent L., and Wang, Andrew H.-J.

Abstract

Various inositide phosphatases participate in the regulation of inositol polyphosphate signaling molecules. Plant phytases are phosphatases that hydrolyze phytate to less-phosphorylated myo-inositol derivatives and phosphate. The phytase from Selenomonas ruminantium shares no sequence homology with other microbial phytases. Its crystal structure revealed a phytase fold of the dual-specificity phosphatase type. The active site is located near a conserved cysteine-containing (Cys241) P loop. We also solved two other crystal forms in which an inhibitor, myo-inositol hexasulfate, is cocrystallized with the enzyme. In the “standby” and the “inhibited” crystal forms, the inhibitor is bound, respectively, in a pocket slightly away from Cys241 and at the substrate binding site where the phosphate group to be hydrolyzed is held close to the −SH group of Cys241. Our structural and mutagenesis studies allow us to visualize the way in which the P loop-containing phytase attracts and hydrolyzes the substrate (phytate) sequentially.

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23. Preliminary X-ray diffraction analysis of octaprenyl pyrophosphate synthase crystals from Thermotoga maritima and Escherichia coli.

Author

Guo RT, Ko TP, Chou CC, Shr HL, Chu HM, Tsai YH, Liang PH, and Wang AH

Subjects
Alkyl and Aryl Transferases genetics, Amino Acid Sequence, Bacterial Proteins chemistry, Bacterial Proteins genetics, Crystallization, Crystallography, X-Ray, Dimerization, Escherichia coli genetics, Models, Molecular, Molecular Sequence Data, Protein Structure, Secondary, Protein Subunits, Recombinant Proteins chemistry, Recombinant Proteins genetics, Sequence Alignment, Sequence Homology, Amino Acid, Thermotoga maritima genetics, Alkyl and Aryl Transferases chemistry, Escherichia coli enzymology, Thermotoga maritima enzymology
Abstract

Octaprenyl pyrophosphate synthase (OPPs) catalyzes the condensation of five isopentenyl pyrophosphates with farnesyl pyrophosphate to generate C(40) octaprenyl pyrophosphate. The enzymes from the hyperthermophilic bacterium Thermotoga maritima and from the mesophilic Escherichia coli were expressed in E. coli and the recombinant proteins were purified and crystallized. The T. maritima OPPs crystals belong to space group P42(1)2, with unit-cell parameters a = b = 151.53, c = 69.72 A. The E. coli OPPs crystals belong to space group C222(1), with unit-cell parameters a = 247.66, b = 266.10, c = 157.93 A. Diffraction data were collected at 100 K using synchrotron radiation and an in-house X-ray source. Structure determination of T. maritima OPPs has been carried out using MIR data sets at 2.8 A resolution. The asymmetric unit contains one dimer. An initial model with 280 residues per subunit has been built and refined to 2.28 A resolution. It shows mostly helical structure and resembles that of avian farnesyl pyrophosphate synthase.

Published
2003
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