4ehm

RabGGTase in complex with covalently bound Psoromic acid

spinqualitylabelsall models 4ehm, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ehm is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, PJA, ZN 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. Publication Abstract from PubMed Post-translational attachment of geranylgeranyl isoprenoids to Rab GTPases, the key organizers of intracellular vesicular transport, is essential for their function. Rab geranylgeranyl transferase (RabGGTase) is responsible for prenylation of Rab proteins. Recently, RabGGTase inhibitors have been proposed to be potential therapeutics for treatment of cancer and osteoporosis. However, the development of RabGGTase selective inhibitors is complicated by its structural and functional similarity to other protein prenyltransferases. Herein we report identification of the natural product psoromic acid (PA) that potently and selectively inhibits RabGGTase with an IC(50) of 1.3 muM. Structure-activity relationship analysis suggested a minimal structure involving the depsidone core with a 3-hydroxyl and 4-aldehyde motif for binding to RabGGTase. Analysis of the crystal structure of the RabGGTase:PA complex revealed that PA forms largely hydrophobic interactions with the isoprenoid binding site of RabGGTase and that it attaches covalently to the N-terminus of the alpha subunit. We found that in contrast to other protein prenyltransferases, RabGGTase is autoinhibited through N-terminal (alpha)His2 coordination with the catalytic zinc ion. Mutation of (alpha)His dramatically enhances the reaction rate, indicating that the activity of RabGGTase is likely regulated in vivo. The covalent binding of PA to the N-terminus of the RabGGTase alpha subunit seems to potentiate its interaction with the active site and explains the selectivity of PA for RabGGTase. Therefore, psoromic acid provides a new starting point for the development of selective RabGGTase inhibitors. Psoromic Acid is a Selective and Covalent Rab-Prenylation Inhibitor Targeting Autoinhibited RabGGTase.,Deraeve C, Guo Z, Bon RS, Blankenfeldt W, Dilucrezia R, Wolf A, Menninger S, Stigter EA, Wetzel S, Choidas A, Alexandrov K, Waldmann H, Goody RS, Wu YW J Am Chem Soc. 2012 May 2;134(17):7384-91. Epub 2012 Apr 22. PMID:22480322 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Geranylgeranyl transferase 3D structures

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