4GTS

Engineered RabGGTase in complex with BMS analogue 16

4GTS の概要

• エントリーDOI: 10.2210/pdb4gts/pdb
• 関連するPDBエントリー: 4GTM 4GTO 4GTP 4GTQ 4GTR 4GTT 4GTV
• 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, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 75782.60

構造登録者

Guo, Z.,Stigter, E.A.,Bon, R.S.,Waldmann, H.,Blankenfeldt, W.,Goody, R.S. (登録日: 2012-08-29, 公開日: 2012-10-24, 最終更新日: 2023-11-08)

主引用文献

Stigter, E.A.,Guo, Z.,Bon, R.S.,Wu, Y.W.,Choidas, A.,Wolf, A.,Menninger, S.,Waldmann, H.,Blankenfeldt, W.,Goody, R.S.
Development of Selective, Potent RabGGTase Inhibitors
J.Med.Chem., 55:8330-8340, 2012

PubMed Abstract: Members of the Ras superfamily of small GTPases are frequently mutated in cancer. Therefore, inhibitors have been developed to address the acitivity of these GTPases by inhibiting their prenylating enzymes FTase, GGTase I, and RabGGTase. In contrast to FTase and GGTase I, only a handful of RabGGTase inhibitors have been developed. The most active RabGGTase inhibitor known until recently was an FTase inhibitor which hit RabGGTase as an off-target. We recently reported our efforts to tune the selectivity of these inhibitors toward RabGGTase. Here we describe an extended set of selective inhibitors. The requirements for selective RabGGTase inhibitors are described in detail, guided by multiple crystal structures. In order to relate in vitro and cellular activity, a high-throughput assay system to detect the attachment of [(3)H]geranylgeranyl groups to Rab was used. Selective RabGGTase inhibition allows the establishment of novel drug discovery programs aimed at the development of anticancer therapeutics.

PubMed: 22963166
DOI: 10.1021/jm300624s

実験手法

X-RAY DIFFRACTION (2.45 Å)