4F3C

Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with butyl-thio-DADMe-Immucillin-A

4F3C の概要

• エントリーDOI: 10.2210/pdb4f3c/pdb
• 関連するPDBエントリー: 4F1W 4F2P 4F2W 4F3K
• 分子名称: 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase, (3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-[(butylsulfanyl)methyl]pyrrolidin-3-ol, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: l-methionine biosynthetic process from s-adenosylmethionine, l-methionine salvage from methylthioadenosine, 5'-methylthioadenosine/s-adenosylhomocysteine nucleosidase, adenosylhomocysteine nucleosidase activity, methylthioadenosine nucleosidase activity, acting on glycosyl bonds, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Salmonella enterica subsp. enterica serovar Choleraesuis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53505.29

構造登録者

Haapalainen, A.M.,Thomas, K.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (登録日: 2012-05-09, 公開日: 2013-05-01, 最終更新日: 2024-02-28)

主引用文献

Haapalainen, A.M.,Thomas, K.,Tyler, P.C.,Evans, G.B.,Almo, S.C.,Schramm, V.L.
Crystal structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Salmonella enterica with butyl-thio-DADMe-Immucillin-A
Structure, 21:963-974, 2013

PubMed Abstract: Accumulation of 5'-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines, and production of quorum-sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans and a target for quorum sensing because MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogs of MTA and SAH explain the structural contacts causing pM binding affinity for the inhibitor and reveal a "water-wire" channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited this discovery by the design and synthesis of tailored modifications of the currently existing transition state analogs to fill this site. This site was not anticipated in MTAN structures. Tailored inhibitors with dissociation constants of 5 to 15 pM are characterized.

PubMed: 23685211
DOI: 10.1016/j.str.2013.04.009

実験手法

X-RAY DIFFRACTION (1.93 Å)