1I41

CYSTATHIONINE GAMMA-SYNTHASE IN COMPLEX WITH THE INHIBITOR APPA

1I41 の概要

• エントリーDOI: 10.2210/pdb1i41/pdb
• 関連するPDBエントリー: 1qgn
• 分子名称: CYSTATHIONINE GAMMA-SYNTHASE, 2-[(3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHYL)-IMINO]-5-PHOSPHONO-PENT-3-ENOIC ACID (2 entities in total)
• 機能のキーワード: plp-dependent enzyme, homotetramer, inhibitor complex, appa, lyase
• 由来する生物種: Nicotiana tabacum (common tobacco)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 581906.52

構造登録者

Steegborn, C.,Laber, B.,Messerschmidt, A.,Huber, R.,Clausen, T. (登録日: 2001-02-19, 公開日: 2001-09-05, 最終更新日: 2023-08-09)

主引用文献

Steegborn, C.,Laber, B.,Messerschmidt, A.,Huber, R.,Clausen, T.
Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novel inhibitor.
J.Mol.Biol., 311:789-801, 2001

PubMed Abstract: Cystathionine gamma-synthase catalyzes the committed step of methionine biosynthesis. This pathway is unique to microorganisms and plants, rendering the enzyme an attractive target for the development of antimicrobials and herbicides. We solved the crystal structures of complexes of cystathionine gamma-synthase (CGS) from Nicotiana tabacum with inhibitors of different compound classes. The complex with the substrate analog dl-E-2-amino-5-phosphono-3-pentenoic acid verifies the carboxylate-binding function of Arg423 and identifies the phosphate-binding pocket of the active site. The structure shows the function of Lys165 in specificity determination and suggests a role for the flexible side-chain of Tyr163 in catalysis. The importance of hydrophobic interactions for binding to the active-site center is highlighted by the complex with 3-(phosphonomethyl)pyridine-2-carboxylic acid. The low affinity of this compound is due to the non-optimal arrangement of the functional groups binding to the phosphate and carboxylate-recognition site, respectively. The newly identified inhibitor 5-carboxymethylthio-3-(3'-chlorophenyl)-1,2,4-oxadiazol, in contrast, shows the highest affinity to CGS reported so far. This affinity is due to binding to an additional active-site pocket not used by the physiological substrates. The inhibitor binds to the carboxylate-recognition site, and its tightly bent conformation enables it to occupy the novel binding pocket between Arg423 and Ser388. The described structures suggest improvements for known inhibitors and give guidelines for the development of new lead compounds.

PubMed: 11518531
DOI: 10.1006/jmbi.2001.4880

実験手法

X-RAY DIFFRACTION (3.2 Å)