Mossessova E, Corpina RA, Goldberg J.Crystal
structure of ARF1*Sec7 complexed with Brefeldin A and its
implications for the guanine nucleotide exchange mechanism.
Mol Cell. 2003 Dec;12(6):1403-11.
Howard Hughes Medical Institute, Structural Biology Program,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New
York, NY 10021, USA.
ARF GTPases are activated by guanine nucleotide exchange factors
(GEFs) of the Sec7 family that promote the exchange of GDP for
GTP. Brefeldin A is a fungal metabolite that binds to the
ARF1*GDP*Sec7 complex and blocks GEF activity at an early stage
of the reaction, prior to guanine nucleotide release. The
crystal structure of the ARF1*GDP*Sec7* Brefeldin A
complex shows that Brefeldin A binds at the
protein-protein interface to inhibit conformational changes in
ARF1 required for Sec7 to dislodge the GDP molecule. Based on a
comparative analysis of the inhibited complex, nucleotide-free
ARF1*Sec7 and ARF1*GDP, we suggest that, in addition to forcing
nucleotide release, the ARF1-Sec7 binding energy is used to open
a cavity on ARF1 to facilitate the rearrangement of hydrophobic
core residues between the GDP and GTP conformations. Thus, the
Sec7 domain may act as a dual catalyst, facilitating both
nucleotide release and conformational switching on ARF proteins.
PMID: 14690595
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