3DZ7

Human AdoMetDC with 5'-[(carboxamidomethyl)methylamino]-5'-deoxy-8-methyladenosine

3DZ7 の概要

• エントリーDOI: 10.2210/pdb3dz7/pdb
• 関連するPDBエントリー: 1I72 1I79 1I7B 1I7C 1I7M 1JEN 3DZ2 3DZ3 3DZ4 3DZ5 3DZ6
• 分子名称: S-adenosylmethionine decarboxylase beta chain, S-adenosylmethionine decarboxylase alpha chain, 1,4-DIAMINOBUTANE, ... (5 entities in total)
• 機能のキーワード: complexes of adometdc with 8-substituted ligands, decarboxylase, lyase, pyruvate, s-adenosyl-l-methionine, spermidine biosynthesis, zymogen, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38820.08

構造登録者

Bale, S.,McCloskey, D.E.,Pegg, A.E.,Secrist III, J.A.,Guida, W.C.,Ealick, S.E. (登録日: 2008-07-29, 公開日: 2009-03-10, 最終更新日: 2024-11-13)

主引用文献

McCloskey, D.E.,Bale, S.,Secrist III, J.A.,Tiwari, A.,Moss III, T.H.,Valiyaveettil, J.,Brooks, W.H.,Guida, W.C.,Pegg, A.E.,Ealick, S.E.
New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine
J.Med.Chem., 52:1388-1407, 2009

PubMed Abstract: S-adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C(8)-substituted adenine analogues bound in the active site.

PubMed: 19209891
DOI: 10.1021/jm801126a

実験手法

X-RAY DIFFRACTION (1.91 Å)