The structural basis of the activation of Ras by Sos.
The crystal structure of human H-Ras complexed with the Ras guanine-nucleotide-exchange-factor region of the Son of sevenless (Sos) protein has been determined at 2.8 A resolution. The normally tight interaction of nucleotides with Ras is disrupted by Sos in two ways. First, the insertion into Ras of an alpha-helix from Sos results in the displacement of the Switch 1 region of Ras, opening up the nucleotide-binding site. Second, side chains presented by this helix and by a distorted conformation of the Switch 2 region of Ras alter the chemical environment of the binding site for the phosphate groups of the nucleotide and the associated magnesium ion, so that their binding is no longer favoured. Sos does not impede the binding sites for the base and the ribose of GTP or GDP, so the Ras-Sos complex adopts a structure that allows nucleotide release and rebinding.
Boriack-Sjodin
P A
PA
Laboratory of Molecular Biophysics, The Rockefeller University, New York, New York 10021, USA.
Margarit
S M
SM
Bar-Sagi
D
D
Kuriyan
J
J
D001665:Binding Sites; D002384:Catalysis; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D020963:GTP Phosphohydrolase-Linked Elongation Factors / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010444:Peptide Elongation Factor Tu / Q000737:chemistry / Q000378:metabolism; D010445:Peptide Elongation Factors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020664:Son of Sevenless Proteins; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D010445:Peptide Elongation Factors; D020664:Son of Sevenless Proteins; C023512:elongation factor Ts; D006147:Guanine; D006160:Guanosine Triphosphate; D020963:GTP Phosphohydrolase-Linked Elongation Factors; D010444:Peptide Elongation Factor Tu; D018631:ras Proteins