Browsing by Author "Cheng, Wen-Chi"

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A Compact Dual Notched Bands CPW-Fed Slot Antenna
(2018-01-01)
Lin, Chu-Huan
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Cheng, Wen-Chi
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Wu, Sung-Jung
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Tarng, Jenn-Hwan
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電信工程研究所
A compact dual notched bands CPW-fed slot antenna is presented. The antenna consists of a wideband CPW-fed slot antenna and four connected slots which can create the impedance mismatch in the unwanted bands. Furthermore, the evolution of the proposed antenna is used to illustrate the band notched operation. The measured results agreed with the simulated results confirm the good omnidirectional radiation patterns with flat gains in the wanted bands but strong gain suppression in the unwanted bands. The proposed antenna can be used in the 2G/5GHz WLAN operation with over 14 dB gain suppression in 2.78-3.36 GHz and 4.03-4.76 GHz bands. The proposed antenna can be easily integrated with other mobile communication devices for its small size, 27(L) X 21 (W) mm(2), and planar structure is suitable for multiband wireless applications.
Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries
(2012-02-29)
Hsu, Kai-Cheng
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Cheng, Wen-Chi
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Chen, Yen-Fu
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Wang, Hung-Jung
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Li, Ling-Ting
Members of protein families often share conserved structural subsites for interaction with chemically similar moieties despite low sequence identity. We propose a core site-moiety map of multiple proteins (called CoreSiMMap) to discover inhibitors and mechanisms by profiling subsite-moiety interactions of immense screening compounds. The consensus anchor, the subsite-moiety interactions with statistical significance, of a CoreSiMMap can be regarded as a "hot spot" that represents the conserved binding environments involved in biological functions. Here, we derive the CoreSiMMap with six consensus anchors and identify six inhibitors (IC50 < 8.0 mu M) of shikimate kinases (SKs) of Mycobacterium tuberculosis and Helicobacter pylori from the NCI database (236,962 compounds). Studies of site-directed mutagenesis and analogues reveal that these conserved interacting residues and moieties contribute to pocket-moiety interaction spots and biological functions. These results reveal that our multi-target screening strategy and the CoreSiMMap can increase the accuracy of screening in the identification of novel inhibitors and subsite-moiety environments for elucidating the binding mechanisms of targets.
Crystal Structure of Shikimate Dehydrogenase from Helicobacter Pylori.
(2009-01-01)
Cheng, Wen-Chi
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Lin, Shuang-Chih
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Wang, Hung-Jung
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Yang, Jinn-Moon
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Lin, Jong-Yih
Pathway-based Screening Strategy for Multitarget Inhibitors of Diverse Proteins in Metabolic Pathways
(2013-07-01)
Hsu, Kai-Cheng
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Cheng, Wen-Chi
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Chen, Yen-Fu
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Wang, Wen-Ching
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Yang, Jinn-Moon
Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of "one-disease, one-target, one-drug". The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermore, single-target inhibitors are often susceptible to drug resistance and are ineffective for complex diseases such as cancers. Therefore, a new strategy is required for enriching the hit rate and identifying multitarget inhibitors. To address these issues, we propose the pathway-based screening strategy (called PathSiMMap) to derive binding mechanisms for increasing the hit rate and discovering multitarget inhibitors using site-moiety maps. This strategy simultaneously screens multiple target proteins in the same pathway; these proteins bind intermediates with common substructures. These proteins possess similar conserved binding environments (pathway anchors) when the product of one protein is the substrate of the next protein in the pathway despite their low sequence identity and structure similarity. We successfully discovered two multitarget inhibitors with IC50 of <10 mu M for shikimate dehydrogenase and shikimate kinase in the shikimate pathway of Helicobacter pylori. Furthermore, we found two selective inhibitors (IC50 of <10 mu M) for shikimate dehydrogenase using the specific anchors derived by our method. Our experimental results reveal that this strategy can enhance the hit rates and the pathway anchors are highly conserved and important for biological functions. We believe that our strategy provides a great value for elucidating protein binding mechanisms and discovering multitarget inhibitors.
Structure, Mechanistic Action, and Essential Residues of a GH-64 Enzyme, Laminaripentaose-producing beta-1,3-Glucanase
(2009-09-25)
Wu, Hsin-Mao
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Liu, Sheng-Wen
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Hsu, Ming-Tsung
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Hung, Chiu-Lien
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Lai, Chun-Chieh
Laminaripentaose-producing beta-1,3-glucanase (LPHase), a member of glycoside hydrolase family 64, cleaves a long-chain polysaccharide beta-1,3-glucan into specific pentasaccharide oligomers. The crystal structure of LPHase from Streptomyces matensis DIC-108 was solved to 1.62 angstrom resolution using multiple-wavelength anomalous dispersion methods. The LPHase structure reveals a novel crescent-like fold; it consists of a barrel domain and a mixed (alpha/beta) domain, forming a wide-open groove between the two domains. The liganded crystal structure was also solved to 1.80 angstrom, showing limited conformational changes. Within the wide groove, a laminaritetraose molecule is found to sit in an electronegatively charged central region and is proximal to several conserved residues including two carboxylates (Glu(154) and Asp(170)) and four other sugar-binding residues (Thr156, Asn(158), Trp(163), and Thr(167)). Molecular modeling using a laminarihexaose as a substrate suggests roles for Glu(154) and Asp(170) as acid and base catalysts, respectively, whereas the side chains of Thr(156), Asn(158), and Trp(163) demarcate subsite +5. Site-directed mutagenesis of Glu(154) and Asp(170) confirms that both carboxylates are essential for catalysis. Together, our results suggest that LPHase uses a direct displacement mechanism involving Glu(154) and Asp(170) to cleave a beta-1,3-glucan into specific alpha-pentasaccharide oligomers.
Structures of Helicobacter pylori Shikimate Kinase Reveal a Selective Inhibitor-Induced-Fit Mechanism
(2012-03-16)
Cheng, Wen-Chi
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Chen, Yen-Fu
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Wang, Hung-Jung
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Hsu, Kai-Cheng
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Lin, Shuang-Chih
Shikimate kinase (SK), which catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid in the presence of ATP, is the enzyme in the fifth step of the shikimate pathway for biosynthesis of aromatic amino acids. This pathway is present in bacteria, fungi, and plants but absent in mammals and therefore represents an attractive target pathway for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here we investigated the detailed structure-activity relationship of SK from Helicobacter pylori (HpSK). Site-directed mutagenesis and isothermal titration calorimetry studies revealed critical conserved residues (D33, F48, R57, R116, and R132) that interact with shikimate and are therefore involved in catalysis. Crystal structures of HpSK center dot SO4, R57A, and HpSK center dot shikimate-3-phosphate center dot ADP show a characteristic three-layer architecture and a conformationally elastic region consisting of F48, R57, R116, and R132, occupied by shikimate. The structure of the inhibitor complex, E114A.162535, was also determined, which revealed a dramatic shift in the elastic LID region and resulted in conformational locking into a distinctive form. These results reveal considerable insight into the active-site chemistry of SKs and a selective inhibitor-induced-fit mechanism.