Crystal structure of ARF1•Sec7 complexed with Brefeldin A and its implications for the guanine nucleotide exchange mechanism Journal Article


Authors: Mossessova, E.; Corpina, R. A.; Goldberg, J.
Article Title: Crystal structure of ARF1•Sec7 complexed with Brefeldin A and its implications for the guanine nucleotide exchange mechanism
Abstract: ARF GTPases are activated by guanine nucleotide exchange factors (GEFs) of the Sec7 family that promote the exchange of GDP for GTP. Brefeldin A (BFA) 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• BFA complex shows that BFA 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.
Keywords: binding affinity; protein conformation; protein domain; protein function; complex formation; protein protein interaction; protein binding; enzyme activation; binding site; crystal structure; models, molecular; crystallography, x-ray; binding sites; arf protein; protein structure; protein family; structure analysis; guanosine triphosphate; protein structure, quaternary; macromolecular substances; guanine nucleotide exchange factors; guanosine diphosphate; guanine nucleotide exchange factor; hydrophobicity; protein synthesis inhibitors; adp-ribosylation factor 1; humans; article; brefeldin a
Journal Title: Molecular Cell
Volume: 12
Issue: 6
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2003-12-01
Start Page: 1403
End Page: 1411
Language: English
DOI: 10.1016/s1097-2765(03)00475-1
PUBMED: 14690595
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 12 September 2014 -- Source: Scopus
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