Development of selective RabGGTase inhibitors and crystal structure of a RabGGTase-inhibitor complex

Max-Planck-Institut für molekulare Physiologie, Abt. Physikalische Biochemie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Angewandte Chemie International Edition (Impact Factor: 11.26). 02/2008; 47(20):3747-50. DOI: 10.1002/anie.200705795
Source: PubMed

ABSTRACT Ende des Transfers: Ausgehend von der Struktur von Pepticinnamin E wurden Inhibitoren der Rab-Geranylgeranyltransferase (RabGGTase) mit zellulärer Aktivität entwickelt. Die erste Kristallstruktur des Enzyms im Komplex mit einem Inhibitor wird vorgestellt (siehe die Struktur des Inhibitors und seine Positionierung im aktiven Zentrum des Enzyms). Die Ergebnisse sind wichtig für chemisch-biologische Studien zur Prenylierung und zum vesikulären Transport und zur Beteiligung von RabGGTase an der Entstehung von Krankheiten.

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    • "Both RGGT and Rab proteins have recently been implicated in numerous diseases including cancer, neurological disorders, bacterial and viral infections [13e15]. To date a few classes of RGGT inhibitors have been identified, including PC derivatives of BPs [4] [7] [11] [12], tripeptide analogues [16] [17], compounds derived from GGTase 1 inhibitors, with pentasubstituted pyrrolidine analogs [18], compounds Abbreviations: PC, phosphonocarboxylate; BP, bisphosphonate; RGGT, Rab geranylgeranyl transferase, Rab GGTase, GGTase 2; TAG tunnel, a tunnel adjacent to GGPP binding site in RGGT; FTase, farnesyl transferase; FPPS, farnesyl pyrophosphate synthase, farnesyl diphosphate synthase; GGTase 1, geranylgeranyl transferase 1; NFSI, N-fluoro-N-(phenylsulfonyl) benzenesulfonamide. * Corresponding author. "
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