3HXE

Engineered RabGGTase in complex with a peptidomimetic inhibitor (compound 37)

3HXE の概要

• エントリーDOI: 10.2210/pdb3hxe/pdb
• 関連するPDBエントリー: 3HXB 3HXC 3HXD 3HXF
• 分子名称: Geranylgeranyl transferase type-2 subunit alpha, Geranylgeranyl transferase type-2 subunit beta, ZINC ION, ... (6 entities in total)
• 機能のキーワード: protein prenylation inhibition, transferase
• 由来する生物種: Rattus norvegicus (rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76191.20

構造登録者

Guo, Z.,Alexandrov, K.,Waldmann, H.,Goody, R.S.,Blankenfeldt, W. (登録日: 2009-06-20, 公開日: 2009-09-08, 最終更新日: 2024-02-21)

主引用文献

Tan, K.T.,Guiu-Rozas, E.,Bon, R.S.,Guo, Z.,Delon, C.,Wetzel, S.,Arndt, S.,Alexandrov, K.,Waldmann, H.,Goody, R.S.,Wu, Y.W.,Blankenfeldt, W.
Design, synthesis, and characterization of Peptide-based rab geranylgeranyl transferase inhibitors
J.Med.Chem., 52:8025-8037, 2009

PubMed Abstract: Rab geranylgeranyl transferase (RabGGTase) catalyzes the attachment of geranylgeranyl isoprenoids to Rab guanine triphosphatases, which are key regulators in vesicular transport. Because geranylgeranylation is required for proper function and overexpression of Rabs has been observed in various cancers, RabGGTase may be a target for novel therapeutics. The development of selective inhibitors is, however, difficult because two related enzymes involved in other cellular processes exist in eukaryotes and because RabGGTase recognizes protein substrates indirectly, resulting in relaxed specificity. We report the synthesis of a peptidic library based on the farnesyl transferase inhibitor pepticinnamin E. Of 469 compounds investigated, several were identified as selective for RabGGTase with low micromolar IC(50) values. The compounds were not generally cytotoxic and inhibited Rab isoprenylation in COS-7 cells. Crystal structure analysis revealed that selective inhibitors interact with a tunnel unique to RabGGTase, implying that this structural motif is an attractive target for improved RabGGTase inhibitors.

PubMed: 19894725
DOI: 10.1021/jm901117d

実験手法

X-RAY DIFFRACTION (1.95 Å)