4CD3

RnNTPDase2 X4 variant in complex with PSB-071

4CD3 の概要

• エントリーDOI: 10.2210/pdb4cd3/pdb
• 関連するPDBエントリー: 4CD1
• 分子名称: ECTONUCLEOSIDE TRIPHOSPHATE DIPHOSPHOHYDROLASE 2, 1-AMINO-4-(3-METHYLPHENYL)AMINO-9,10-DIOXO-9,10-DIHYDROANTHRACENE-2-SULFONATE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: hydrolase, apyrase, atpase, purinergic signalling, drug design, inhibitor, ntpdase
• 由来する生物種: RATTUS NORVEGICUS (NORWAY RAT)
• 細胞内の位置: Isoform 1: Cell membrane; Multi-pass membrane protein (By similarity): O35795
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51493.87

構造登録者

Zebisch, M.,Schaefer, P.,Straeter, N. (登録日: 2013-10-29, 公開日: 2014-02-12, 最終更新日: 2024-10-23)

主引用文献

Zebisch, M.,Baqi, Y.,Schafer, P.,Muller, C.E.,Strater, N.
Crystal Structure of Ntpdase2 in Complex with the Sulfoanthraquinone Inhibitor Psb-071.
J.Struct.Biol., 185:336-, 2014

PubMed Abstract: In many vertebrate tissues CD39-like ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) act in concert with ecto-5'-nucleotidase (e5NT, CD73) to convert extracellular ATP to adenosine. Extracellular ATP is a cytotoxic, pro-inflammatory signalling molecule whereas its product adenosine constitutes a universal and potent immune suppressor. Interference with these ectonucleotidases by use of small molecule inhibitors or inhibitory antibodies appears to be an effective strategy to enhance anti-tumour immunity and suppress neoangiogenesis. Here we present the first crystal structures of an NTPDase catalytic ectodomain in complex with the Reactive Blue 2 (RB2)-derived inhibitor PSB-071. In both of the two crystal forms presented the inhibitor binds as a sandwich of two molecules at the nucleoside binding site. One of the molecules is well defined in its orientation. Specific hydrogen bonds are formed between the sulfonyl group and the nucleoside binding loop. The methylphenyl side chain functionality that improved NTPDase2-specificity is sandwiched between R245 and R394, the latter of which is exclusively found in NTPDase2. The second molecule exhibits great in-plane rotational freedom and could not be modelled in a specific orientation. In addition to this structural insight into NTPDase inhibition, the observation of the putative membrane interaction loop (MIL) in two different conformations related by a 10° rotation identifies the MIL as a dynamic section of NTPDases that is potentially involved in regulation of catalysis.

PubMed: 24462745
DOI: 10.1016/J.JSB.2014.01.005

実験手法

X-RAY DIFFRACTION (2.19 Å)