3EQ8

Prolyl oligopeptidase complexed with R-Pro-(decarboxy-Pro)-Type inhibitors

3EQ8 の概要

• エントリーDOI: 10.2210/pdb3eq8/pdb
• 関連するPDBエントリー: 3EQ7 3EQ9
• 分子名称: Prolyl endopeptidase, 1-{3-oxo-3-[(2S)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidin-1-yl]propyl}-3-phenylquinoxalin-2(1H)-one (3 entities in total)
• 機能のキーワード: hydrolase, protease, serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Sus scrofa (pig)
• 細胞内の位置: Cytoplasm: P23687
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 81308.87

構造登録者

Kanai, K.,Aranyi, P.,Bocskei, Z.,Ferenczy, G.,Harmat, V.,Simon, K.,Naray-Szabo, G.,Hermecz, I. (登録日: 2008-09-30, 公開日: 2009-08-25, 最終更新日: 2023-11-01)

主引用文献

Kanai, K.,Aranyi, P.,Bocskei, Z.,Ferenczy, G.,Harmat, V.,Simon, K.,Batori, S.,Naray-Szabo, G.,Hermecz, I.
Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules
J.Med.Chem., 51:7514-7522, 2008

PubMed Abstract: Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.

PubMed: 19006380
DOI: 10.1021/jm800944x

実験手法

X-RAY DIFFRACTION (2.73 Å)