3hxc | pdb_00003hxc

Engineered RabGGTase in complex with a peptidomimetic inhibitor (compound 8)

spinqualitylabelsall models 3hxc, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3hxc is a 2 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BD6, CA, ZN Related: 3hxb, 3hxd, 3hxe, 3hxf Activity: Protein geranylgeranyltransferase type II, with EC number 2.5.1.60 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PGTA_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. [PGTB2_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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Design, synthesis, and characterization of peptide-based rab geranylgeranyl transferase inhibitors.,Tan KT, Guiu-Rozas E, Bon RS, Guo Z, Delon C, Wetzel S, Arndt S, Alexandrov K, Waldmann H, Goody RS, Wu YW, Blankenfeldt W J Med Chem. 2009 Dec 24;52(24):8025-37. PMID:19894725 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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