1. Laboratories of Molecular Biophysics, New York, New York 10021, USA
2. Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA
3. Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA

Correspondence to: Correspondence and requests for materials should be addressed to J.K. The atomic coordinates have been deposited in the Brookhaven Protein Data Bank under code 1BKD.

Abstract

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 Å resolution. The normally tight interaction of nucleotides with Ras is disrupted by Sos in two ways. First, the insertion into Ras of an -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.

1. Laboratories of Molecular Biophysics, New York, New York 10021, USA
2. Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA
3. Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA

Correspondence to: Correspondence and requests for materials should be addressed to J.K. The atomic coordinates have been deposited in the Brookhaven Protein Data Bank under code 1BKD.