3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design

Wang, Jing‐Fang; Wei, Dong; Li, Lin; Zheng, Shigang; Li, Yi Xue; Chou, Kuo Chen

doi:10.1016/j.bbrc.2007.01.185

Cited by 111 publications

(44 citation statements)

References 43 publications

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“…For further information about protein folding, refer to a recent review [214] and the references cited therein. Again, although it is quite successful to predict the 3D structure of a protein according to the homology modeling approach [2,215] as reflected by a series of homology-modeled proteins for drug development [84,147,[149][150][151]153,[216][217][218][219][220][221][222][223][224][225][226], a hurdle exists when the query protein does not have any structure-known homologous protein in the existing databases [3].…”

Section: Pfp-predmentioning

confidence: 99%

REVIEW : Recent advances in developing web-servers for predicting protein attributes

Chou¹,

Shen²

2009

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277

173

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Recent advance in large-scale genome sequencing has generated a huge volume of protein sequences. In order to timely utilize the information hidden in these newly discovered sequences, it is highly desired to develop computational methods for efficiently identifying their various attributes because the information thus obtained will be very useful for both basic research and drug development. Particularly, it would be even more useful and welcome if a user-friendly web-server could be provided for each of these methods. In this minireview, a systematic introduction is presented to highlight the development of these web-servers by our group during the last three years.

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Section: Pfp-predmentioning

confidence: 99%

REVIEW : Recent advances in developing web-servers for predicting protein attributes

Chou¹,

Shen²

2009

Self Cite

277

173

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“…45 Furthermore, Arg335 was predicted to form binding pockets for ligands of CEC, fluvoxamine and lescol. 46,47 It seems that the R335Q substitution in CYP2C19 not only destabilizes protein secondary structure but also alters its affinity for substrates. Although the function of CYP2C19*24 remains to be further investigated, we could still speculate that it possibly has the characteristic of diminished protein activity.…”

Section: 25mentioning

confidence: 99%

Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese

Zhou

Lin

et al. 2009

Pharmacogenomics J

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The cytochrome P450 2C19 and 2D6 enzymes are predominantly found in the human liver, and have important functions in the metabolism of many different classes of commonly used drugs. Their genetic polymorphisms give rise to both important interethnic variability in metabolism and the risk of treatment failure or dose-dependent drug toxicity. To investigate genetic polymorphisms in CYP2C19 and CYP2D6 genes in Han Chinese, we sequenced regions of the 5 0 flanking region, exon, intron and 3 0 UTR from these two genes using 100 unrelated healthy Chinese Hans. We detected 48 genetic variants in CYP2C19. A total of 15 of them are novel, including two polymorphisms in putative transcriptional factor-binding sites. The CYP2C19*1, *2, *3, *4, *17, *23, *24 and *25 alleles have frequencies of 67.5, 25.5, 2, 0.5, 3, 0.5, 0.5 and 0.5%, respectively. Based on computational predictions, three novel alleles (CYP2C19*23, *24 and *25) are deleterious mutations of the CYP2C19 protein. In CYP2D6, we identified 84 different polymorphisms, including 18 novel single-nucleotide polymorphisms. One novel polymorphism is located in a potential cis-regulatory element of the gene. The allele frequencies of CYP2D6*1, *2, *4, *5, *6, *10, *14, *21, *36, *41, *43, *52 and *71 are 18.5, 14, 1, 7, 0.5, 49, 1.5, 0.5, 1, 4, 0.5, 1 and 1.5%, respectively. The occurrence of CYP2D6 duplication is 0.5%. The novel CYP2D6*71 is anticipated as a putative poor metabolizer allele. We also performed linkage disequilibrium analysis and observed strong linkage disequilibrium spanning of the CYP2C19 and CYP2D6 regions. In addition, network analysis showed that 15 haplotypes of CYP2C19 and 22 of CYP2D6 are classified into five and three groups, respectively. Comparisons of allele frequency distributions revealed significant interethnic and intraethnic differences in these two genes. In conclusion, this study revealed that CYP2C19 and CYP2D6 have a complicated allele composition and distinct frequency distribution in Han Chinese.

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“…Such a criterion was originally used to define the binding pocket of ATP in the Cdk5-Nck5a* complex [76] that has later proved quite useful in identifying functional domains and stimulating the relevant truncation experiments [81]. The similar approach has also been used to define the binding pockets of other receptor-ligand interactions [11,15,25,78,90,91,94,104,106].…”

Section: Resultsmentioning

confidence: 99%

“…The segment match approach has also been successfully used to predict the 3D structures for CARDs (caspase recruitment domains) of Apaf-1, Ced-4 and Ced-3 based on the solution structure of the RAIDD CARD [82], as well as the â -secretase zymogen [83]; the structural information derived from the latter has convincingly elucidated the mechanism why the prodomain of â -secretase did not suppress the activity like in a strict zymogen, as reported by Benjannet et al [84] and Shi et al [85]. Furthermore, the segment match approach was also used to develop the 3D structures of extracellular domains for the subtypes 1, 2, 3, and 5 of GABA-A receptors [9], BACE2 [86], GFAT [10], human ion channels [87], 7 nicotinic acetylcholine receptor [11], cathepsin-E [88], human G alpha 13 and human TXA2 receptor [12], DNA-CBF3b complex [89], H5N1-NA [90] as well as CYP2C19 [17,91], greatly stimulating the development of the related areas (see, e.g., [17,[92][93][94]). …”

Section: Methodsmentioning

confidence: 99%

Molecular Modeling Studies on NADP-Dependence of Candida Tropicalis Strain Xylose Reductase

Wang¹,

Wei²,

Du³

et al. 2008

TOBIOIJ

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Abstract:The Candida tropicalis strain CT1799 xylose reductase (XR) with protein ID ABG49458.1 is a kind of NADPH-dependent xylose reductase. It could be used to construct recombinant Saccharomyces cerevisiae strain for utilizing xylose and producing alcohol. To investigate the interaction mechanism of XR with NADP and NAD, the 3D (dimensional) structure for XR was developed. With the 3D structure, the molecular docking operations were conducted to find the most favorable bindings of XR with NADP and NAD. Based on these results, the binding pockets of XR for NADP and NAD have been explicitly defined, respectively. It was observed that Asn278 and Arg282 of XR could form hydrogen bonds with both NADP and NAD that were bonded to the same site of XR with some competitive relationship. However, according to the binding energies and conformational fitting, NADP is a more favorable coenzyme to XR. All these findings may explain why XR is NADP-dependent. The findings can be used to guide mutagenesis studies, providing useful clues to modify the enzyme for improving the utilization of xylose in producing alcohol. In addition, because the human aldose reductases have the functions to reduce the open chain form of glucose to sorbitol, a process physiologically significant for diabetic patients at the time that their blood glucose levels are elevated, the information gained through this study may also stimulate the development of new strategies for the therapeutic treatment of diabetes.

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3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design

Cited by 111 publications

References 43 publications

REVIEW : Recent advances in developing web-servers for predicting protein attributes

REVIEW : Recent advances in developing web-servers for predicting protein attributes

Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese

Molecular Modeling Studies on NADP-Dependence of Candida Tropicalis Strain Xylose Reductase

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