Crystal Structure of Catechol O-Methyltransferase Complexed with Nitecapone
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- Iijima Hiroshi
- School of Pharmacy, Nihon University
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- Takebe Katsuki
- Oral and Maxillofacial Surgery II, Osaka University Graduate School of Dentistry
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- Suzuki Mamoru
- Institute for Protein Research, Osaka University
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- Kobayashi Hiroko
- School of Pharmacy, Nihon University
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- Takamiya Tomoko
- School of Pharmacy, Nihon University
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- Saito Hiroaki
- School of Pharmacy, Nihon University
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- Niwa Norio
- School of Pharmacy, Nihon University
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- Kuwada-Kusunose Takao
- School of Dentistry at Matsudo, Nihon University
書誌事項
- タイトル別名
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- Crystal Structure of Catechol <i>O</i>-Methyltransferase Complexed with Nitecapone
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<p>Catechol O-methyltransferase (COMT) is known as an important drug-target protein in the field of Parkinson’s disease. All clinically approved COMT inhibitors bring a 5-substituted-3-nitrocatechol ring as a pharmacophore, and they bind to COMT with S-adenosylmethionine (SAM) and an Mg2+ ion to form a quaternary complex (COMT/SAM/Mg2+/inhibitor). However, structural information about such quaternary complexes is only available for a few inhibitors. Here, a new crystal structure of COMT complexed with nitecapone (5), SAM and Mg2+ is revealed. Comparison of the structures of these complexes indicates that conformation of the catechol binding pocket is almost constant regardless of structure of the inhibitors. The only restriction of the side chain of inhibitors (i.e., the substituent at the 5-position of 3-nitrocatechol) seems to be that it does not make steric repulsion with COMT. However, recent crystallographic and biochemical studies suggest that COMT is a flexible protein, and its conformational flexibility seems crucial for its catalytic process. Based on this information, implications of these quaternary inhibitor complexes were investigated. Met 40 in the α2α3-loop makes atomic contacts with SAM or S-adenosylhomocysteine and the 3-position of the catechol inhibitor. This interaction seems to play a critical role in the affinity of the inhibitor and to stabilize the COMT/SAM/Mg2+/nitrocatechol inhibitor complex by fixing the flexible α2α3-loop.</p>
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 68 (5), 447-451, 2020-05-01
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390285300155315200
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- NII論文ID
- 130007838793
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 030401513
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- PubMed
- 32378542
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- 抄録ライセンスフラグ
- 使用不可