1 research outputs found
Psoromic Acid is a Selective and Covalent Rab-Prenylation Inhibitor Targeting Autoinhibited RabGGTase
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<sub>50</sub> 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 <sub>α</sub>His2 coordination with the catalytic
zinc ion. Mutation of <sub>α</sub>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