2BRP

Crystal structure of S. pneumoniae hyaluronate lyase in complex with W249b

2BRP の概要

• エントリーDOI: 10.2210/pdb2brp/pdb
• 関連するPDBエントリー: 1C82 1EGU 1F9G 1LOH 1LXK 1N7N 1N7O 1N7P 1N7Q 1N7R 1OJM 1OJN 1OJO 1OJP 1W3Y 2BRV 2BRW
• 分子名称: HYALURONATE LYASE, SULFAMIC ACID 1-DECYL-2-(4-SULFAMOYLOXYPHENYL)-1H-INDOL-6-YL ESTER, D-xylose, ... (5 entities in total)
• 機能のキーワード: (alfa5/alfa5) barrel, lyase, peptidoglycan-anchor
• 由来する生物種: STREPTOCOCCUS PNEUMONIAE
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 85016.31

構造登録者

Rigden, D.J.,Jedrzejas, M.J. (登録日: 2005-05-10, 公開日: 2006-04-24, 最終更新日: 2023-12-13)

主引用文献

Rigden, D.J.,Botzki, A.,Nukui, M.,Mewbourne, R.B.,Lamani, E.,Braun, S.,von Angerer, E.,Bernhardt, G.,Dove, S.,Buschauer, A.,Jedrzejas, M.J.
Design of new benzoxazole-2-thione-derived inhibitors of Streptococcus pneumoniae hyaluronan lyase: structure of a complex with a 2-phenylindole.
Glycobiology, 16:757-765, 2006

PubMed Abstract: The bacterial hyaluronan lyases (Hyals) that degrade hyaluronan, an important component of the extracellular matrix, are involved in microbial spread. Inhibitors of these enzymes are essential in investigation of the role of hyaluronan and Hyal in bacterial infections and constitute a new class of antibiotics against Hyal-producing bacteria. Recently, we identified 1,3-diacetylbenzimidazole-2-thione and related molecules as inhibitors of streptococcal Hyal. One of such compounds, 1-decyl-2-(4-sulfamoyloxyphenyl)-1-indol-6-yl sulfamate, was co-crystallized in a complex with Streptococcus pneumoniae Hyal and its structure elucidated. The resultant X-ray structure demonstrates that this inhibitor fits in the enzymatic active site via interactions resembling the binding mode of the natural hyaluronan substrate. X-ray structural analysis also indicates binding interactions with the catalytic residues and those of a catalytically essential hydrophobic patch. An IC50 value of 11 microM for Hyal from Streptococcus agalactiae (strain 4755) qualifies this phenylindole compound as one of the most potent Hyal inhibitors known to date. The structural data suggested a similar binding mode for N-(3-phenylpropionyl)-benzoxazole-2-thione. This new compound's inhibitory properties were confirmed resulting in discovery of yet another Hyal inhibitor (IC50 of 15 microM). These benzoxazole-2-thiones constitute a new class of inhibitors of bacterial Hyals and are well suited for further optimization of their selectivity, potency, and pharmacokinetic properties.

PubMed: 16638841
DOI: 10.1093/glycob/cwj116

実験手法

X-RAY DIFFRACTION (2 Å)