4gts
Engineered RabGGTase in complex with BMS analogue 16Engineered RabGGTase in complex with BMS analogue 16
Structural highlights
FunctionPGTA_RAT Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to both cysteines in Rab proteins with an -XXCC, -XCXC and -CCXX C-terminal, such as RAB1A, RAB3A and RAB5A respectively. Publication Abstract from PubMedMembers 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. Development of Selective, Potent RabGGTase Inhibitors.,Stigter EA, Guo Z, Bon RS, Wu YW, Choidas A, Wolf A, Menninger S, Waldmann H, Blankenfeldt W, Goody RS J Med Chem. 2012 Oct 11;55(19):8330-40. doi: 10.1021/jm300624s. Epub 2012 Oct 3. PMID:22963166[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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