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Structural Basis of Single Nucleotide Polymorphisms in Cytochrome P450 2C9
https://repo.qst.go.jp/records/48421
https://repo.qst.go.jp/records/48421e8356c70-9ffe-49c4-ae01-52d73b52f3cd
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-01-11 | |||||
| タイトル | ||||||
| タイトル | Structural Basis of Single Nucleotide Polymorphisms in Cytochrome P450 2C9 | |||||
| 言語 | ||||||
| 言語 | jpn | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
前川, 京子(同志社女子大学)
× 前川, 京子(同志社女子大学)× 安達, 基泰× 松澤, 由美子(国立医薬品食品衛生研究所)× Zhang(The, Scripps Research Institute) Qinghai× 黒木, 良太(日本原子力研究開発機構)× B., Shah(Albany College of Pharmacy and Health Sciences) Manish× 安達 基泰 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Single nucleotide polymorphisms in drug metabolizing Cytochrome P450 (CYP) enzymes are important contributors to inter-individual variability in drug response and metabolism leading to drug-drug interactions and adverse reactions. Despite the abundant structural and functional information available regarding CYPs in multiple species, the structural basis of polymorphisms is still lacking. The crystal structures of a major human drug metabolizing enzyme CYP2C9 and its variants, *3 (I359L) and *30 (A477T), were solved with an anti-hypertensive drug losartan. The complexes of the wild-type (WT) enzyme and the *30 variant demonstrated binding of three molecules of losartan, whereas two losartan molecules were bound to the *3 complex. The losartan bound at the periphery in all the structures revealed a signature sequence of conserved residues as potential substrate recognition site. In the *3 variant, the I359L substitution located far away from the active site remarkably influenced the residue sidechains near the active site and the access channel, resulting in significant differences in losartan binding. Furthermore, the T477 substitution in *30 variant illustrated hydrogen-bonding interaction with the sidechain of Q214, which reoriented markedly compared to the WT complex. The structures yield insight into the implications of genetic polymorphisms and provide useful framework to understand precision medicine. | |||||
| 書誌情報 |
Biochemistry 巻 56, 号 41, p. 5476-5480, 発行日 2017-10 |
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| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1021/acs.biochem.7b00795 | |||||
