4EHM

RabGGTase in complex with covalently bound Psoromic acid

Summary for 4EHM

• Entry DOI: 10.2210/pdb4ehm/pdb
• Descriptor: Geranylgeranyl transferase type-2 subunit alpha, Geranylgeranyl transferase type-2 subunit beta, 4-formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid, ... (6 entities in total)
• Functional Keywords: prenylation, inhibition, psoromic acid, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 75528.20

Authors

Guo, Z.,Deraeve, C.,Bon, R.S.,Alexandrov, K.,Waldmann, H.,Wu, Y.W.,Goody, R.S.,Blankenfeldt, W. (deposition date: 2012-04-02, release date: 2012-05-30, Last modification date: 2017-08-09)

Primary citation

Deraeve, C.,Guo, Z.,Bon, R.S.,Blankenfeldt, W.,Dilucrezia, R.,Wolf, A.,Menninger, S.,Stigter, E.A.,Wetzel, S.,Choidas, A.,Alexandrov, K.,Waldmann, H.,Goody, R.S.,Wu, Y.W.
Psoromic Acid is a Selective and Covalent Rab-Prenylation Inhibitor Targeting Autoinhibited RabGGTase
J.Am.Chem.Soc., 134:7384-7391, 2012

PubMed Abstract: 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 μM. 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 α subunit. We found that in contrast to other protein prenyltransferases, RabGGTase is autoinhibited through N-terminal (α)His2 coordination with the catalytic zinc ion. Mutation of (α)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 α 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.

PubMed: 22480322
DOI: 10.1021/ja211305j

Experimental method

X-RAY DIFFRACTION (2.2 Å)